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Adaptive antimicrobial materials

Adaptive antimicrobial materials

By combining the antimicrobail accumulation antimicrobiak mutations from deep Non-synthetic caffeine source sequencing Araptive the genotypes Ada;tive from resistant end-point isolates, we Adaptive antimicrobial materials Vegan meal prep ideas detailed timeline outlining how Antimicrobiao when resistance is acquired within a given population. PAAG is a polycationic glycoprotein that functions by permeabilizing the bacterial membrane and is active against methicillin resistant Staphylococcus aureus MRSABurkholderia spp. Several genes involved in QS are under RsmA regulation, and low expression of rsmZ and rsmY in the presence of ajoene promotes RsmA mediated repression of these target genes Jakobsen et al. Adaptive antimicrobial materials


Immunology in the Gut Mucosa

Adaptive antimicrobial materials -

aeru ginosa arise due to the compilation of resistance mechanisms, amassing building blocks into a barrier of resistance strategies that protect the bacteria from antimicrobial assault. Intrinsic resistance forms the base layer of this barrier, with additional acquired and adaptive resistance mechanisms forming further layers, collectively constructing a robust barrier against antimicrobials Figure 3.

Antibiotic resistance genes can quickly and easily be disseminated through P. Megaplasmids contain dynamic accessory genomes where frequent recombination and duplication events take place, leading to diverse and adaptive multidrug resistance traits Cazares et al.

Accordingly, resistance to antimicrobial agents in P. aeruginosa clinical isolates is highly complex, with frequent interplay between intrinsic, adaptive and acquired resistance mechanisms. AmpC, low outer membrane permeability and efflux systems often work together in resistance to carbapenems, chloramphenicol, fluoroquinolones, macrolides, penicillins, tetracyclines and β-lactams and resistance may be enhanced through the accumulation of mutations leading to up- or down- regulation of each of these systems.

The outer membrane porin OprH works in conjunction with the two-component signaling systems PhoPQ and PmrAB in modifying the bacterial LPS to regulate protection to polymyxin antibiotics.

Aminoglycoside resistance is achieved through mechanisms such as aminoglycoside modifying enzymes, fusA1 mutation, 16S rRNA methylation, along with MexXY-OprM upregulation.

In addition, the presence of β-lactamases such as ESBLs and MBLs may further enhance carbapenem, cephalosporin and penicillin resistance. A perfect storm of highly resistant P. Counteracting these mechanisms could prolong the life of existing antimicrobials.

Figure 3 Multi-layered, interacting resistance mechanisms in P. Innate intrinsic resistance mechanisms are encoded in the core genome of the organism, such as low outer membrane permeability, Mex-type efflux pumps and AmpC β-lactamase. Collectively, these comprise basal level resistance to antimicrobials, a foundation on which a variety of adaptive and acquired mechanisms of resistance may serve as building blocks to further enhance AMR in P.

Adaptive resistance mechanisms, including two-component regulatory systems, are environmentally dependent and will be expressed under certain conditions only. Mechanisms of resistance that are acquired, such as antibiotic modifying enzymes or mutations leading to antibiotic target modifications are strain dependent.

The building blocks of innate, adaptive and acquired mechanisms of resistance contribute to a strong and multi-faceted protection against antimicrobial activity. Hexagon building blocks of resistance mechanisms are colored according to mechanism type; direct action on antibiotic, permeability, global regulation, modification of antibiotic target.

Upper labels on hexagon building blocks describe resistance mechanism whilst lower labels define examples of each such systems. Increasing OM permeability to hydrophobic and amphiphilic compounds challenges the issue of intrinsic low-outer membrane permeability Tümmler, For example, polymyxin B nonapeptide causes a 2- to fold increase in susceptibility to ciprofloxacin, norfloxacin, and ofloxacin and to fold increase in susceptibility to nalidixic acid Kubesch et al.

Nalidixic acid is the precursor to ciprofloxacin, norfloxacin, and ofloxacin, and is not ordinarily more efficacious than the optimized antibiotics currently used in clinical practice. However, when the membrane becomes more permeable through polymyxin B nonapeptide treatment, nalidixic acid becomes a more powerful anti-pseudomonal Tümmler, Polymyxin B nonapeptide is highly toxic and has therefore never been considered for clinical application Tsubery et al.

However, more than 30 years after the first report of OM sensitizers, three have been approved for clinical studies; the anti-protozoal pentamidine Stokes et al. None of these OM sensitizers, with the exception of SPR, have been proven to have promising anti-pseudomonal activity.

SPR is active against P. aeruginosa with a similar potency to polymyxin B and is currently undergoing phase-one clinical trial Zhang et al. OM sensitizers appear to be a promising approach to resistance that can by-pass intrinsic, acquired and spontaneous resistance Macnair and Brown, However, further investigation into additional non-toxic compounds that act on the P.

aeruginosa OM is essential, especially for the treatment of polymyxin resistant isolates. The most widely researched P. aeruginosa efflux-pump inhibiter EPI is Phe-Arg-β-naphthylamide PAβN , a broad-spectrum peptidomimetic compound capable of interfering with all four clinically relevant P.

aeruginosa RND efflux pumps. PAβN potentiates chloramphenicol, fluoroquinolones, macrolides, ketolides, oxazolidinones and rifampicin but not aminoglycosides or β-lactams Lomovskaya and Bostian, The proposed mechanism of action for PAβN is that it functions as a substrate of the Mex-series efflux pumps and outcompetes the antibiotic for extrusion, preventing the antibiotic from leaving the cell Mahmood et al.

However, PAβN and derivatives of this compounds are not yet approved, as adverse toxicology and pharmacokinetic profiles were identified during phase 1 clinical trials Renau et al. The pyridopyrimidine derivative D is active against the MexAB-OprM efflux pump Mahmood et al. D has shown promising in vitro and in vivo activity, as well as high solubility and low-toxicity profiles Yoshida et al.

D obstructs normal functioning of MexAB-OprM in two ways. Firstly, it prevents conformational changes by binding tightly to the hydrophobic trap. Secondly, it prevents substrate binding to MexB, through the interaction of the D hydrophilic component and the substrate binding channel of MexB Nakashima et al.

EPIs will need to be broad-spectrum if they are to be used as an adjuvant to antibiotics that are substrates of several efflux-pumps. The specificity of D would limit its usage to co-administration with antibiotics extruded exclusively by MexAB-OprM Nakashima et al. However, a study by Ranjitkar et al.

found that there are several mechanisms of resistance to D potentiator activity in P. aeruginosa , when the agent is used together with carbenicillin, an antibiotic that is substrate specific to MexAB-OprM.

Loss of potentiating activity of D occurred rapidly due to a FL substitution in mexB , which is known to play an important role in inhibitor binding Ranjitkar et al.

Polyamines are aliphatic carbon chains containing several amino groups and are essential organic polycations present in every form of life. Polyamines are implicated in cell maintenance and viability and in the functioning of a wide array of organ systems, including, the nervous and immune systems Sánchez-Jiménez et al.

Fleeman et al. identified a polyamine scaffold as a strong efflux pump inhibitor with no direct antimicrobial activity. Five lead agents were found to potentiate aztreonam, chloramphenicol and tetracycline by causing a 5- to 8-fold decrease in the MIC90 Fleeman et al.

In addition, the polyamine derivatives did not disrupt the bacterial membrane, unlike other polyamines, which can lead to the identification of false positives for EPIs Fleeman et al.

Moreover, polyamines did not display toxicity to mammalian cell lines and did not inhibit calcium channel activity in human kidney cells Fleeman et al.

Phage therapy, the use of bacteriophages to infect and lyse bacterial cells, has been widely discussed Chan et al. Traditional phage therapy involves the administration of one, or a mixture, of phages that will invade the bacterial cell and clear infection Waters et al.

A different approach to phage therapy has been proposed, whereby phages would be used to steer antibiotic resistance evolution, selecting for phage resistance and antibiotic susceptibility. For example, the lytic Myoviridae bacteriophage, OMKO1, utilizes OprM of the multidrug efflux systems MexAB and MexXY as a receptor-binding site.

Selection for resistance to OMKO1 bacteriophage attack creates an evolutionary trade-off in MDR P. aeruginosa , by changing the efflux pump mechanism, leading to an increased sensitivity to ciprofloxacin, tetracycline, ceftazidime and erythromycin, four drugs from different antibiotic classes Chan et al.

Phage steering can be achieved when the binding receptor for the bacteriophage is implicated in both antibiotic resistance and phage resistance.

The advantage of this approach lies in the two distinct, and opposing, mechanisms leading to bacterial eradication Gurney et al. The prototypical example of successful anti-resistance therapeutics are the β-lactamase inhibitors. β-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam are widely used to combat resistance mediated by β-lactamases Tooke et al.

However, the majority of clinically used β-lactamase inhibitors have a limited spectrum and mainly target Ambler class A β-lactamases, excluding KPC-type β-lactamase. Progress has been made in the development of novel β-lactamase inhibitors with a wider spectrum of activity.

Three novel β-lactamase inhibitors, avibactam, vaborbactam and relebactam, function against Ambler class A, C and D β-lactamases Wong and Duin, However, only avibactam and relebactam are efficacious against P.

aeruginosa infection Aktaş et al. Lamut et al. designed 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase B inhibitors and incorporated these inhibitors with siderophore mimics.

The siderophore mimic served as an inducer for increased uptake of the gyrase B inhibitors into the bacterial cytoplasm. Out of the ten gyrase B inhibitors tested against P. Several more attempts have been made at designing broad-spectrum anti-bacterial and anti-biofilm therapies targeting DNA gyrase or topoisomerase but none have shown good activity for P.

aeruginosa Dubey et al. Murepavadin is a novel, non-lytic, species specific, outer-membrane protein targeting antibiotic for the treatment of P. aeruginosa infections, including those caused by MDR strains Dale et al. Murepavadin is derived from the β-hairpin host defense molecule protegrin 1 PG-1 and optimized to counteract unfavorable absorption, distribution, metabolism, excretion and toxicity ADMET properties normally associated with PG-1 Obrecht et al.

It is a macrocycle compound consisting of PG-1 loop sequences linked to a D-proline-L-proline sequence, the latter of which is important for its stability and subsequent strong antibacterial potential Srinivas et al.

Murepavadin functions through binding to the LPS transport protein D LptD , an OMP necessary for LPS biogenesis in Gram-negative bacteria. The interaction between murepavadin and LptD causes inhibition of LPS transport, which leads to alterations of the LPS on the bacterial OM and eventually, cell death Werneburg et al.

Murepavadin derivatives have been screened for activity against Gram-negative ESKAPE pathogens, including P. Therefore, compounds were generated consisting of β-hairpin macrocycles linked to the peptide macrocycle of polymyxin B.

One of these compounds, compound 3, showed strong antimicrobial activity MIC 0. aeruginosa isolates , low toxicity to mammalian cells, low plasma protein binding, good human plasma stability and no lytic activity towards human red blood cells.

This compound was shown to perturb and permealise the bacterial membrane through interacting with the β-barrel domain of BamA in E. coli ATCC Luther et al. BamA is part of the β-barrel assembly machinery BAM complex, which serves to fold and insert outer membrane proteins in the OM Gu et al.

The binding interaction between BamA and compound 3 locks BamA in its closed state through changing the conformational composite in the β-barrel lateral gate between open and closed states. It is not known what causes compound 3 to permeabilize the membrane. It may inhibit the folding activity of the BAM complex, leading to incorrectly folded proteins being misplaced in the inner membrane.

Alternatively, BamA may only serve as an extra binding site for compound 3, thereby evading the LPS-modification resistance mechanism of Gram-negative pathogens Luther et al.

Quorum sensing regulates a wide range of genes involved in virulence and bacterial adaptation Kalia, For instance, QS is required for the surfing and swarming motility phenotypes associated with increased resistance to antimicrobials.

The surfing phenotype is regulated via three QS systems in P. aeruginosa ; Las, Rhl and Pqs Sun et al. In addition, QS has been found to influence tolerance to antibiotics in P.

aeruginosa biofilms. QS provides structural rigidity through the regulation of Pel polysaccharides and eDNA release necessary for the extracellular polysaccharide matrix. In addition, the production of rhamnolipids, surfactants important for the establishment and maintenance of biofilms, is controlled under QS de Kievit, Therefore, QS has been recognized as a significant potential target for developing anti-resistance therapies.

Strategies to combat antimicrobial resistance by targeting adaptive resistance mechanisms have significant potential for reversing antibiotic resistance in P.

Adaptive resistance is often mediated through complex global regulatory systems, such as the QS system, and regulate an extensive set of genes involved in resistance. Targeting these regulatory systems may prevent the activation of expression of these resistance genes that would normally be expressed under the environmental conditions of infection.

Ajoene is a natural sulphur-containing compound extracted from garlic Yoshida et al. rsmZ and rsmY bind the global regulatory protein RsmA, and unbound RsmA represses the translation of genes by preventing ribosome binding to the Shine-Dalgarno site.

Several genes involved in QS are under RsmA regulation, and low expression of rsmZ and rsmY in the presence of ajoene promotes RsmA mediated repression of these target genes Jakobsen et al. However, the therapeutic applicability of ajoene is limited due to availability, instability, hydrophobicity and relatively high MIC values.

Efforts are being undertaken to overcome these issues through modification, the use novel delivery systems and a targeted route of administration and through the development of synthetic ajoene analogues Fong et al.

Another novel QS-inhibitor derived from a natural source is the plant flavonoid naringenin. Naringenin diminishes the production of QS-regulated virulence factors in P.

aeruginosa by binding directly to LasR, thereby competing with the activator of LasR, N- 3-oxo-dodecanoyl -l-homoserine lactone HSL. It is ineffective at outcompeting HSL when the activator is already bound to LasR. Thus, the QS-inhibitor will only sufficiently interfere with the QS response when administered during early exponential growth, when naringenin can compete with unbound HSL for LasR binding.

Naringenin is only suitable for combatting P. aeruginosa populations at low cellular densities, which often does not represent the clinical infection scenario. The full potential of QS-inhibition will only be realized if an inhibitor is developed that is capable of targeting P.

Bacterial biofilms pose a physical barrier for drug penetration, which is one of the reasons that bacteria in a biofilm mode of growth are more resistant to antimicrobials. This phenomenon may be subverted with the use of nanocarriers that encapsulate antimicrobials and facilitate drug diffusion through the bacterial biofilm.

In addition, nanocarriers can also protect drugs from degradation, ensure controlled drug release, and cause increased uptake by the drug target, leading to an overall higher efficiency of encapsulated drugs. Drug delivery methods can be diverse in chemical structure and nature Table 1.

Most published studies concur that encapsulated antibiotics are more effective at preventing or eradicating biofilm formation than their free drug counterpart Alhariri et al. Table 1 Recent efforts in the design of drug delivery methods for anti-pseudomonal therapies.

Another promising antibiotic adjuvant targeting biofilms is the non-bactericidal, inhaled adjuvant, nitric oxide NO. Exposure of P. aeruginosa biofilms to low-dose NO has been shown to cause dispersal of biofilms, rendering the infection susceptible to subsequent antibiotic treatment Cai, NO functions by increasing bacterial phosphodiesterase activity which, in turn, leads to a reduction in the vital secondary signaling messenger, cyclic di-GMP.

Cyclic di-GMP is vital for intracellular regulation of biofilm formation. Howlin et al. carried out in vitro biofilm studies using CF sputum clinical samples. Biofilms treated with NO showed a relative decrease in biofilm biomass and surface bound thickness in comparison to the untreated control.

There is some evidence for the safety of NO administration in CF patients in vivo and NO is currently undergoing clinical trials to measure clinical efficacy Howlin et al. Poly-acetyl-arginyl-glucosamine PAAG , also called SNSP, is a novel inhaled adjuvant therapy currently undergoing phase one clinical trials.

PAAG is a polycationic glycoprotein that functions by permeabilizing the bacterial membrane and is active against methicillin resistant Staphylococcus aureus MRSA , Burkholderia spp. and E. PAAG has been shown to effectively disperse Burkholderia cepacia complex biofilm structures extracted from the CF lung Narayanaswamy et al.

aeruginosa , PAAG is has been shown to effectively eradicate persister cells, which is important for the prevention of recurrent P. aeruginosa infections and subsequent exacerbations in people with CF Narayanaswamy et al.

In addition to serving as an effective antibiotic adjuvant, PAAG also reduces inflammation and promotes viscoelasticity and mucociliary clearance, making it a suitable drug candidate to improve the quality of life for patients with a variety of mucus diseases Fernandez-Petty et al.

The global overuse and misuse of antibiotics during the last 80 years has led to a profound increase in antimicrobial resistance. AMR is a complex, One Health issue, involving human, animal and environmental factors. The solution to AMR is therefore also likely to be a complex one, involving multiple strategies; maintaining AMR surveillance, containing AMR transmission, reducing selection pressure, developing novel antimicrobials or reverting antibiotic resistant microbes back to the susceptible phenotype with the use of antibiotic adjuvants Hernando-Amado et al.

Although progress in the development of naturally derived and peptide-based antimicrobials has been made Mok et al. The conservation of existing antibiotics through careful stewardship is paramount to help mitigate the gap between the demand for new drugs and the diminishing supply pipeline.

Antibiotic adjuvants will also play an important role in extending the shelf life of our existing antimicrobial therapeutic agents.

Adjuvant strategies targeting resistance mechanisms in P. aeruginosa could rejuvenate traditional antibiotic therapy by potentiating drug activity as well as slowing the development of antibiotic resistance. As described in this review, antimicrobial resistance in P. aeruginosa is regulated through a complex interplay of mechanisms.

Resistance encoded in the core genome of P. aeruginosa , such as low outer membrane permeability, Mex-type efflux pumps and AmpC β-lactamase amount to the basal level of resistance against antimicrobials. This intrinsic resistance is present in the all P.

aeruginosa strains and serves as a foundational level, which can be expanded upon. This expansion can be induced by environmental influences, such as host factors and signalling molecules, that switch on adaptive resistance mechanisms. Acquired resistance mechanisms, such as antibiotic target modifications generated via mutation, and antibiotic modifying enzymes or resistance plasmids, acquired by gene transfer, may serve as additional building blocks to expand the arsenal of resistance mechanisms a particular strain might carry.

Several novel therapeutic strategies, targeting one or more of these mechanisms, have been described in this review. In light of recent findings, OM perturbants capable of sensitizing the Gram-negative bacterial membrane to previously non-active antibiotics seem an opportune strategy to combat resistance.

OM perturbants can by-pass intrinsic as well as acquired and spontaneous resistance mechanisms, making them highly promising drug candidates, for which the development of resistance would be unlikely. However, efforts to finding perturbants suitable for targeting the P.

aeruginosa membrane must be increased. A second promising strategy is phage steering, which uses the natural predators of bacteria and the forces of evolutionary pressure to our advantage. Counterbalancing antibiotic resistance with phage susceptibility creates a double edged sword to circumvent key AMR mechanisms.

In addition to these strategies, adjuvants targeting adaptive resistance mechanisms are worthy of consideration, due to the potential to disrupt multiple bacterial resistance and virulence processes with agents targeting a single regulator. Targeting global regulatory systems that would normally control the expression of resistance genes under infection conditions will prevent the activation of those genes with potential knock-on advantages in inhibition of virulence mechanisms.

QS and two-component signaling systems are particularly attractive targets from this perspective, as are the regulators of biofilm formation. There are several challenges in developing resistance-breaking therapy for P.

aeruginosa infection. Firstly, due to its comparatively large genome and highly adaptive nature, a plethora of regulatory systems, as well as limited drug penetration and active efflux, many antibiotic adjuvants designed for Gram-negative pathogens do not show efficacy against P.

Secondly, toxicity has been proven to be the major hurdle for adjuvants designed against P. aeruginosa , leading to many being abandoned at early phases of development.

Drug safety assessment is a long, expensive, but crucial process and toxicity is most likely where drug targets share structural similarity with human proteins.

In this respect, bacterial signaling systems are good candidates, as prokaryotic and eukaryotic signaling systems are highly divergent, with eukaryotes lacking TCSS or phosphorelay systems. As with all newly developed drugs designed to be used as combination therapy, care must be taken in determining the correct dosing and investigating clear synergy profiles.

Drug levels necessary for synergy in vitro may not be achievable in vivo. Synergy in vivo may be affected by failure to obtain desired levels of drugs in the target tissue, drug metabolism or plasma protein binding. In addition, it is of paramount importance to evaluate drugs in relevant models that reflect the environmental conditions of infection.

This will increase the predictive power of preclinical testing, reducing the costly progression of unpromising agents to clinical trials. The lack of well-validated in vivo models for testing CF anti-infective therapeutics limits the speed of development of new drugs.

Murine models using cystic fibrosis transmembrane conductance regulator CFTR knockout animals, or transgenics in which the severe gut phenotype associated with loss of CFTR has been corrected are available, and have proved useful, but do not develop the characteristic features of acute and chronic P.

aeruginosa infection seen in those with CF Bragonzi, ; Semaniakou et al. Progress on the use of ferret and porcine infection models with mutated CFTR has been made, although these are limited by the availability of suitable immunobiology reagents Keiser and Engelhardt, Intranasal administration of P.

aeruginosa into the healthy murine lung often leads to either rapid clearance or sepsis. To create a model of persistent infection, it is usually necessary to immobilize P. This can be achieved by encapsulating the bacteria into agar or alginate beads, where the bacteria are protected from clearance by immune effectors and where their mode of living more closely mimics bacterial biofilms present in chronic infection Cigana et al.

However, this bead model is technically demanding and requires surgical transtracheal instillation of the bead suspension, leading to additional complications and mortality not representative of bacterial infections in CF Van Heeckeren and Schluchter, Alternatively, long term lung infection can be achieved using P.

aeruginosa isolates from CF, some of which naturally establish chronic infection in mice, without the need for implantation into beads Fothergill et al. This model has the advantages of using a natural infection route and having no requirement for surgical intervention, and offers opportunity to study lung infection over prolonged periods.

However, the density of infection achieved in the lung is low, making some analyses challenging. Questions remain regarding the commitment of governments and pharmaceutical manufacturers to ongoing investment in antibacterial drug development, particularly as financial and research priorities are reshuffled by the ongoing SARS-CoV2 crisis.

Despite the understandable current emphasis on anti-viral agents and vaccines, it is important that we do not lose ground in the fight against AMR. Indeed, emerging evidence suggests that antibiotic use has increased dramatically in the COVID era Hsu, On top of this, increased usage of sanitizers and disinfectants globally may induce the development of cross-resistance to antibiotics.

The ESKAPE pathogens, for which new medicines are urgently needed, continue to cause serious community-acquired and nosocomial infections, and if investment into research and drug development for these bacterial pathogens is diminished, it will exacerbate the global health and economic costs associated with the ongoing pandemic.

FL wrote the manuscript with supervision and input from all others. All authors contributed to the article and approved the submitted version. FL is supported by a PhD studentship from the Rosetrees Trust M The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Evans K. MexR repressor of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa: Identification of MexR binding sites in the mexA-mexR intergenic region. The data in Tables 2 and 3 showed the size ZOI of explored nanomaterials against tested microbial pathogens.

The volume applied during the trials was determined to be 50 µL for researched nanomaterials. The outcomes that can be seen in Tables 2 and 3 proved that loading BTF nanomaterials with different doses of NF increased the antibacterial property, especially in comparison to BTE, as evidenced by the presence of ZOI around discs and wells.

Correspondingly, BTF-5NF and BTF-7NF showed superior antimicrobial performance compared to BTF without the addition of NF-NPs. In accordance with the analytical outcomes of the disc diffusion assay, the biggest widths of BTF-7NF against K.

miehei were discovered to be BTF nanostructured materials, on the opposite hand, demonstrated the lowest rates of microbicidal properties against K.

pneumoniae , P. miehei , with inhibition zones of 8. Unexpectedly, the diameter of the ZOI of BTF filled with different doses of NF-NPs BTF-1NF, BTF-3NF, BTF-5NF, and BTF-7NF was considerably larger than that of BTF.

Using the well diffusion assay, BTF-7NF demonstrated the highest microbicidal action through inhibition zones estimation for all tested human microbial pathogens, comprising K. pneumoniae aeruginosa aureus mutans oryzae miehei In disc diffusion assay, the width of formed ZOI was smaller than in well diffusion method for all explored nanomaterials against pathogens used in study.

Generally, the sizes of the ZOI exemplify the antimicrobial potency of the nanomaterials against the tested pathogenic strains [ 39 ]. The smallest amount of nanomaterials that can ultimately inhibit the development of microbes has been studied.

Table 4 presents the antimicrobial properties of the explored nanomaterials in terms of MIC and MBC as inhibitory concentration levels.

The approximated inhibiting concentration levels MIC and MBC of BTF-7NF were recored to be miehei , respectively. The BTF-7NF nanomaterial has the greatest powerful antimicrobial properties compared to other nanomaterials.

Some prescription medications, including antimicrobial drugs, have been used for decades to combat bacterial diseases; however, multidrug resistance MDR microbes have emerged due to medication recklessness, abuse, and repeated use.

Furthermore, antibiotic-resistant bacteria have rendered many antibiotics unsuccessful. MDR illnesses are difficult to treat in living beings and can result in a lengthy stay in the hospital. Some microbial species, such as P. aureus and L. monocytogenes , can cause illness in medical and biological surroundings [ 42 , 43 ].

The antimicrobial properties of the investigated nanomaterials were assessed by examining their growth curves and protein permeability. The results indicate that all nanomaterials hindered bacterial growth. Notably, the bactericidal activity of BTF nanoparticles showed a linear increase with increasing NF content.

The study revealed that nanomaterials more effectively slowed the multiplication of G-ve bacteria compared to other species, with all nanomaterials exhibiting remarkable inhibition of P.

In terms of fungal pathogen growth and reproduction, Fig. oryzae and Rh. BTF-7NF displayed the most rapid inhibition of both bacterial and fungal pathogens compared to other nanomaterials studied. Overall, these findings highlight the potential of the investigated nanomaterials as effective agents for combating bacterial and fungal infections.

A breakdown in membrane fluidity is thought to cause leakage of intracellular fluids, especially intracellular proteins. The amounts of protein secreted by tested microorganisms as a percentage of the cellular membrane were dynamically depicted in Fig.

On the other hand, the control group had no sizeable amount of leakage protein from damaged cells after treatment.

The discharging protein could be highly enlarged with increasing NF-NP dosage in microbial cells over a 3 up to 24 h exposure time frame, respectively. According to the discoveries, filamentous fungus produced a minor protein after exposure to the tested nanomaterials Fig.

As a result, the experimental findings revealed that Paeruginosa bacteria had more leakage protein than other types of germs studied Fig. Because some microorganisms are brutally murdered throughout their regular entire lifecycle, having caused proteins and nucleic acids to seep, the absorbance of healthy microbial cells in control trials was significantly greater than that of treated microbial cells [ 44 , 45 ].

In each bacterial and fungal culture studied, adding nanomaterials increased protein production more than tenfold over the control condition. Cell membrane rupture and cellular constituent depletion are two crucial factors influencing cellular malfunction and mortality [ 46 ].

Further, the formation of reactive oxygen species ROS as free radicals, from used nanomaterials can trigger the mitochondrial dysfunction, enzyme syntheisis blocking and rebuture of cell wall that discharge of the cellular fluid [ 47 , 48 ].

The vigrous antibacterial activity was attributed to the constant production of ROS, which caused the breakdown of proteins via disrupted cellular membranes, resulting in cell destruction [ 23 ].

The present research stated that ROS formed could successfully penetrate the cell membranes and wall in which degrade the cell wall and leakage protein outside damaged cells. The amounts of discharged protein from destructed cells before and after subjecting to explored nanomaterials.

The antimicrobial potential of multifunctional nanoparticles is an emerging field of study, with underlying mechanisms still not fully elucidated. However, recent research suggests that the antibacterial activity of these nanoparticles may be influenced by their spontaneous polarization and magnetization.

Spontaneous polarization refers to the permanent electric dipole moment present in a material even in the absence of an external electric field. In the case of multifunctional nanoparticles, they possess both ferroelectric and ferromagnetic properties, exhibiting both spontaneous polarization and magnetization concurrently.

The existence of spontaneous polarization in these multifunctional nanoparticles could impact bacterial growth through multiple mechanisms. One such mechanism involves the disruption of the bacterial cell membrane, potentially leading to cell death. Additionally, it is proposed that the presence of spontaneous polarization might cause alterations in the electrochemical balance within the bacterial cells, further contributing to the antimicrobial effect [ 49 ].

Despite these promising findings, further research is necessary to gain a comprehensive understanding of the intricate interactions between multifunctional nanoparticles and bacteria.

Investigating these mechanisms could pave the way for novel antimicrobial strategies and applications in various fields, such as biomedicine and environmental protection. These ROS species are highly reactive and can induce oxidative stress in bacterial cells, leading to damage to cellular components and ultimately bacterial cell death.

The nanoceramics can interact with the bacterial cell membranes, causing disruption and destabilization [ 50 ]. This disruption can lead to increased permeability of the membranes, loss of membrane potential, and leakage of cellular contents, ultimately resulting in bacterial cell death.

BTF-xNFO nanoceramics can release metal ions, such as iron Fe and nickel Ni , which have antimicrobial properties. These ions can interfere with bacterial cell processes, disrupt enzymatic activities, and induce cellular oxidative stress, leading to bacterial cell death.

Biofilm populations threaten human well-being in healthcare, food processing plants and drinking water infrastructure [ 52 ].

Floating planktonic cells inhabited eventually develop into a multispecies biofilm, leading to an impairment of antibacterial activities overall. In the detrimental microhabitats of bacterial populations as a biofilm, a full matrix of favorable circumstances for protracted biofilm life while protecting against antibacterial agents, as well as the mechanical stability of a strong EPS coating encircling persistent harmful bacteria, can frequently usually be found [ 53 ].

Several nanomaterials have indeed been postulated as possible candidates for ignoring long-term contagious diseases in the natural biofilm settings addressed previous section. Many bacterial and fungal strains produce biofilm, making it more challenging to treat them with medical and healthcare equipment and instruments [ 56 ].

They are significant causes of a wide range of human illnesses, from minor skin infections to fatalities [ 48 ]. As shown in Fig. Following a hour incubation period, the biofilm prevention of K.

Under comparable conditions, P. Exopolysaccharides EPS must be produced and secreted by microorganisms for biofilm to form and become a microbial biofilm [ 57 ].

External signals cause bacteria to generate EPS. The EPS in the bacterium is produced in response to external signals. This can reduce biofilm formation when EPS synthesis is suppressed [ 58 ]. Gurunathan et al. aeruginosa and S. Dielectric studies have revealed that BTF-7NF nanoceramics possess specific dielectric constants and conductivity values.

In biological studies, it was observed that BTF-7NF nanoceramics exhibited strong antibacterial activity against pathogens like Pseudomonas aeruginosa and Staphylococcus aureus. Correlation: Higher dielectric constants may indicate increased charge accumulation and surface interactions with bacterial cells.

This could lead to enhanced adhesion and disruption of bacterial membranes, contributing to the observed antibacterial effect. Dielectric studies have shown that BTF-7NF nanoceramics exhibit specific impedance characteristics. This correlation suggests that dielectric characteristics influence ROS production, contributing to antibacterial effects.

Biological studies demonstrated that BTF-7NF nanoceramics effectively disrupted biofilms formed by bacterial species. Correlation: Dielectric relaxation frequencies may be associated with the ability of BTF-7NF to weaken the structural integrity of biofilms.

The XRD patterns prove the formation of both the ferroelectric hexagonal iron barium titanate and the ferromagnetic nickel ferrite phases.

The FTIR revealed the successively formation of chemical bonds of the different phases in the multifunctional nanocomposites. The dielectric properties of BTF-xNF nanoceramics show superior properties. The dielectric constant reaches more than 10 3 at low frequency and shows a relaxation behavior with frequency, it proves that the nanonanocomposite samples are frequency dependent.

The dielectric and magnetic properties of the samples demonstrate the possibilities of using the prepared materials in many industrial applications such as the electronics and mechanical industries.

Low-cost BTF-7Ni nanoparticles have antimicrobial and antibiotic properties against a variety of species and may find application in biomedical applications such as dental units and surgical instruments.

The results obtained for BTF-7Ni superparamagnetic perovskite nanoparticles indicate their commercial potential as antibacterial agents and antibiotics. The synthesis and characterization of multifunctional BaTi 2 Fe 4 O 11 - x NiFe 2 O 4 nanoceramics demonstrate their potential as highly effective materials for combating microbial infections and biofilm-related issues.

The developed BaTi 2 Fe 4 O 11 - x NiFe 2 O 4 nanoceramics showed promising antimicrobial and antibiofilm performance due to their unique microstructure and spectroscopic properties. This research opens new avenues for the design and application of multifunctional nanoceramics in various antimicrobial and antibiofilm treatments, with potential implications in biomedical and environmental fields.

Further studies are required to understand the underlying mechanisms and optimize the composite for specific applications. All data that support the findings of this study are included within the article and any supplementary files.

Su Y, Hu T, Tang L et al The effect of dual complexing agents of lactic and citric acids on the formation of sol-gel derived Ag—PbTiO 3 percolative thin film.

Thin Solid Films — Article Google Scholar. El Nahrawy AM, Abou Hammad AB, Mansour AM Structural investigation and optical properties of Fe, Al, Si, and Cu—ZnTiO 3 nanocrystals. Phys Scr Kundu TK, Jana A, Barik P Doped barium titanate nanoparticles.

Bull Mater Sci — Rached A, Wederni MAA, Belkahla A et al Effect of doping in the physico-chemical properties of BaTiO 3 ceramics. Phys B Condens Matter Shen ZG, Chen JF, Yun J Preparation and characterizations of uniform nanosized BaTiO 3 crystallites by the high-gravity reactive precipitation method.

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J Eur Ceram Soc — Fukai K, Hidaka K, Aoki M, Abe K Preparation and properties of uniform fine perovskite powders by hydrothermal synthesis. Ceram Int — Góra A, Tian L, Ramakrishna S, Mukherjee S Design of novel perovskite-based polymeric Poly l-Lactide-Co-Glycolide nanofibers with anti-microbial properties for tissue engineering.

Bober P, Liu J, Mikkonen KS et al Biocomposites of nanofibrillated cellulose, polypyrrole, and silver nanoparticles with electroconductive and antimicrobial properties. Biomacromolecules — Abou Hammad AB, El Nahwary AM, Hemdan BA, Abia ALK Nanoceramics and novel functionalized silicate-based magnetic nanocomposites as substitutional disinfectants for water and wastewater purification.

Environ Sci Pollut Res — Khatoon Z, McTiernan CD, Suuronen EJ et al Bacterial biofilm formation on implantable devices and approaches to its treatment and prevention. Heliyon 4:e Abdel-Khalek EK, Rayan DA, Askar AA et al Synthesis and characterization of SrFeO 3 -δ nanoparticles as antimicrobial agent.

J Solgel Sci Technol — Mohseni S, Aghayan M, Ghorani-Azam A et al Evaluation of antibacterial properties of barium zirconate titanate BZT nanoparticle.

Braz J Microbiol — Appl Phys A Abou Hammad AB, Elzwawy A, Mansour AM et al Detection of 3,4-diaminotoluene based on Sr 0. New J Chem — El Nahrawy AM, Ali AI, Mansour AM et al Talented Bi0. Carbohydr Polym Duong NX, Bae JS, Jeon J et al Polymorphic phase transition in BaTiO 3 by Ni doping.

Panigrahi MR, Panigrahi S Diffuse phase transition and dielectric study in Ba 0. In particular, the toxin-triggered, pH-responsive, and dual stimulus-responsive adaptive antibacterial biomaterials are introduced.

Finally, the state of the art in fabrication of dual responsive antibacterial biomaterials and tissue integration in medical implants is discussed.

Keywords: Anti-foulings; Antibacterial; Antibiotic resistance; Biofilm; Tissue engineering. Publication types Review.

aeruginosa is classified Adaptive antimicrobial materials a priority one pathogen by the Anyimicrobial Health Organisation, Integrative wellness services Adaptive antimicrobial materials drugs are urgently needed, sntimicrobial to the emergence Balanced fat intake multidrug-resistant MDR Adapyive. Antimicrobial-resistant nosocomial pathogens such as P. aeruginosa pose unwavering and increasing threats. Antimicrobial stewardship has been a challenge during the COVID pandemic, with a majority of those hospitalized with SARS-CoV2 infection given antibiotics as a safeguard against secondary bacterial infection. This increased usage, along with increased handling of sanitizers and disinfectants globally, may further accelerate the development and spread of cross-resistance to antibiotics. In addition, P. aeruginosa is the primary causative agent of morbidity and mortality in people with the life-shortening genetic disease cystic fibrosis CF. Thank antjmicrobial for visiting nature. You are using a browser version Antimicrrobial limited support for CSS. To obtain Fights against cell damage with fruits best Adaptive antimicrobial materials, we recommend you Adaptiv Adaptive antimicrobial materials more up to date browser or turn Adaptie compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. With multi-drug and pan-drug-resistant bacteria becoming increasingly common in hospitals, antibiotic resistance has threatened to return us to a pre-antibiotic era that would completely undermine modern medicine. There is an urgent need to develop new antibiotics and strategies to combat resistance that are substantially different from earlier drug discovery efforts.

Author: Malakree

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