Strategies for controlling polymicrobial biofilms: A focus on antibiofilm agents.

Polymicrobial biofilms are among the leading causes of antimicrobial treatment failure. In these biofilms, bacterial and fungal pathogens interact synergistically at the interspecies, intraspecies, and interkingdom levels. Consequently, combating polymicrobial biofilms is substantially more difficult compared to single-species biofilms due to their distinct properties and the resulting potential variation in antimicrobial drug efficiency. In recent years, there has been an increased focus on developing alternative strategies for controlling polymicrobial biofilms formed by bacterial and fungal pathogens. Current approaches for controlling polymicrobial biofilms include monotherapy (using either natural or synthetic compounds), combination treatments, and nanomaterials. Here, a comprehensive review of different types of polymicrobial interactions between pathogenic bacterial species or bacteria and fungi is provided along with a discussion of their relevance. The mechanisms of action of individual compounds, combination treatments, and nanomaterials against polymicrobial biofilms are thoroughly explored. This review provides various future perspectives that can advance the strategies used to control polymicrobial biofilms and their likely modes of action. Since the majority of research on combating polymicrobial biofilms has been conducted in vitro, it would be an essential step in performing in vivo tests to determine the clinical effectiveness of different treatments against polymicrobial biofilms.

Roles of Pseudomonas aeruginosa siderophores in interaction with prokaryotic and eukaryotic organisms.

Pseudomonas aeruginosa is an opportunistic pathogen that produces two types of siderophores, pyoverdine and pyochelin, that play pivotal roles in iron scavenging from the environment and host cells. P. aeruginosa siderophores can serve as virulence factors and perform various functions. Several bacterial and fungal species are likely to interact with P. aeruginosa due to its ubiquity in soil and water as well as its potential to cause infections in plants, animals, and humans. Siderophores produced by P. aeruginosa play critical roles in iron scavenging for prokaryotic species (bacteria) and eukaryotic hosts (fungi, animals, insects, invertebrates, and plants) as well. This review provides a comprehensive discussion of the role of P. aeruginosa siderophores in interaction with prokaryotes and eukaryotes as well as their underlying mechanisms of action. The evolutionary relationship between P. aeruginosa siderophore recognition receptors, such as FpvA, FpvB, and FptA, and those of other bacterial species has also been investigated.

Marine-derived bioactive materials as antibiofilm and antivirulence agents.

Microbial infections are major human health issues, and, recently, the mortality rate owing to bacterial and fungal infections has been increasing. In addition to intrinsic and extrinsic antimicrobial resistance mechanisms, biofilm formation is a key adaptive resistance mechanism. Several bioactive compounds from marine organisms have been identified for use in biofilm therapy owing to their structural complexity, biocompatibility, and economic viability. In this review, we discuss recent trends in the application of marine natural compounds, marine-bioinspired nanomaterials, and marine polymer conjugates as possible therapeutic agents for controlling biofilms and virulence factors. We also comprehensively discuss the mechanisms underlying biofilm formation and inhibition of virulence factors by marine-derived materials and propose possible applications of novel and effective antibiofilm and antivirulence agents.

Attenuation of biofilm and virulence factors of Pseudomonas aeruginosa by tetramethylpyrazine-gold nanoparticles.

Pseudomonas aeruginosa is often identified as the causative agent in nosocomial infections. Their adapted resistance makes them strong towards antimicrobial treatments. They protect and empower their survival behind strong biofilm architecture that works as their armor toward antimicrobial therapy. Additionally, P. aeruginosa generates virulence factors, contributing to chronic infection and recalcitrant phenotypic characteristics. The current study utilizes the benevolence of nanotechnology to develop an alternate technique to control the spreading of P. aeruginosa by limiting its biofilm and virulence development. This study used a natural compound, tetramethylpyrazine, to generate gold nanoparticles. Tetramethylpyrazine-gold nanoparticles (Tet-AuNPs) were presented in spherical shapes, with an average size of 168 ± 52.49 nm and a zeta potential of -12.22 ± 2.06 mV. The minimum inhibition concentration (MIC) of Tet-AuNPs that proved more than 90 % effective in inhibiting P. aeruginosa was 256 µg/mL. Additionally, it also shows antibacterial activities against Staphylococcus aureus (MIC, 256 µg/mL), Streptococcus mutans (MIC, 128 µg/mL), Klebsiella pneumoniae (MIC, 128 µg/mL), Listeria monocytogenes (MIC, 256 µg/mL), and Escherichia coli (MIC, 256 µg/mL). The sub-MIC values of Tet-AuNPs significantly inhibited the early-stage biofilm formation of P. aeruginosa. Moreover, this concentration strongly affected hemolysis, protease activity, and different forms of motilities in P. aeruginosa. Additionally, Tet-AuNPs destroyed the well-established mature biofilm of P. aeruginosa. The expression of genes linked with the biofilm formation and virulence in P. aeruginosa treated with sub-MIC doses of Tet-AuNPs was shown to be significantly suppressed. Gene expression studies support biofilm- and virulence-suppressing effects of Tet-AuNPs at the phenotypic level.

Silver nanoparticles synthesized from Pseudomonas aeruginosa pyoverdine: Antibiofilm and antivirulence agents.

The increasing incidence of antimicrobial resistance exhibited by biofilm-forming microbial pathogens has been recognized as one of the major issues in the healthcare sector. In the present study, nanomaterial-based controlling the biofilm and virulence properties has been considered an alternative approach. Pyoverdine (PVD) isolated from the Pseudomonas aeruginosa was utilized as a biological corona to synthesize silver nanoparticles (AgNPs), which will be helpful in a targeted action to microbial pathogens due to the recognition of the corona of the nanoparticles by the pathogenic membrane. Synthesized PVD-AgNPs were spherical to irregular, with an average size value of 251.87 ± 21.8 nm and zeta potential with a value of -36.51 ± 0.69 mV. The MIC value of PVD-AgNPs towards P. aeruginosa, Listeria monocytogenes, Staphylococcus aureus, Streptococcus mutans, Escherichia coli, and Candida albicans in the standard and host-mimicking media were observed in decreasing order in a multi-fold, such as standard growth media > sputum > synthetic human urine > saliva. Both the initial stage and the well-established biofilms of these microbial pathogens have been effectively inhibited and eradicated by PVD-AgNPs. PVD-AgNPs increase the susceptibility of tetracycline, PVD, and amphotericin B towards established mature mono- and mixed-species biofilms of S. aureus and C. albicans. Additionally, PVD-AgNPs attenuate several virulence properties, such as inhibition of protease activity, motility, and PVD and pyocyanin production in P. aeruginosa. The inhibition of gene expression of biofilm and virulence-associated genes in P. aeruginosa validates its phenotypic effects.

Antibiofilm and antivirulence activities of laminarin-gold nanoparticles in standard and host-mimicking media.

The rapidly rising antimicrobial resistance (AMR) in pathogenic bacteria has become one of the most serious public health challenges, with a high death rate. Most pathogenic bacteria have been recognized as a source of AMR and a primary barrier to antimicrobial treatment failure due to the development of biofilms and the production of virulence factors. In this work, nanotechnology was employed as a substitute method to control the formation of biofilms and attenuate virulence features in Pseudomonas aeruginosa and Staphylococcus aureus. We synthesized biocompatible gold nanoparticles from marine-derived laminarin as potential biofilm and virulence treatments. Laminarin-gold nanoparticles (Lam-AuNPs) have been identified as spherical, 49.84 ± 7.32 nm in size and - 26.49 ± 1.29 mV zeta potential. The MIC value of Lam-AuNPs against several drug-resistant microbial pathogens varied from 2 to 1024 µg/mL in both standard and host-mimicking media. Sub-MIC values of Lam-AuNPs were reported to effectively reduce the production of P. aeruginosa and S. aureus biofilms in both standard and host-mimicking growth media. Furthermore, the sub-MIC of Lam-AuNPs strongly reduced hemolysis, pyocyanin, pyoverdine, protease, and several forms of flagellar and pili-mediated motility in P. aeruginosa. Lam-AuNPs also inhibited S. aureus hemolysis and the production of amyloid fibrils. The Lam-AuNPs strongly dispersed the preformed mature biofilm of these pathogens in a dose-dependent manner. The Lam-AuNPs would be considered an alternative antibiofilm and antivirulence agent to control P. aeruginosa and S. aureus infections. KEY POINTS: • Lam-AuNPs were biosynthesized to control biofilm and virulence. • Lam-AuNPs show effective biofilm inhibition in standard and host-mimicking media. • Lam-AuNPs suppress various virulence factors of P. aeruginosa and S. aureus.

Bacterial extracellular vesicles: Modulation of biofilm and virulence properties.

Microbial pathogens cause persistent infections by forming biofilms and producing numerous virulence factors. Bacterial extracellular vesicles (BEVs) are nanostructures produced by various bacterial species vital for molecular transport. BEVs include various components, including lipids (glycolipids, LPS, and phospholipids), nucleic acids (genomic DNA, plasmids, and short RNA), proteins (membrane proteins, enzymes, and toxins), and quorum-sensing signaling molecules. BEVs play a major role in forming extracellular polymeric substances (EPS) in biofilms by transporting EPS components such as extracellular polysaccharides, proteins, and extracellular DNA. BEVs have been observed to carry various secretory virulence factors. Thus, BEVs play critical roles in cell-to-cell communication, biofilm formation, virulence, disease progression, and resistance to antimicrobial treatment. In contrast, BEVs have been shown to impede early-stage biofilm formation, disseminate mature biofilms, and reduce virulence. This review summarizes the current status in the literature regarding the composition and role of BEVs in microbial infections. Furthermore, the dual functions of BEVs in eliciting and suppressing biofilm formation and virulence in various microbial pathogens are thoroughly discussed. This review is expected to improve our understanding of the use of BEVs in determining the mechanism of biofilm development in pathogenic bacteria and in developing drugs to inhibit biofilm formation by microbial pathogens. STATEMENT OF SIGNIFICANCE: Bacterial extracellular vesicles (BEVs) are nanostructures formed by membrane blebbing and explosive cell lysis. It is essential for transporting lipids, nucleic acids, proteins, and quorum-sensing signaling molecules. BEVs play an important role in the formation of the biofilm's extracellular polymeric substances (EPS) by transporting its components, such as extracellular polysaccharides, proteins, and extracellular DNA. Furthermore, BEVs shield genetic material from nucleases and thermodegradation by packaging it during horizontal gene transfer, contributing to the transmission of bacterial adaptation determinants like antibiotic resistance. Thus, BEVs play a critical role in cell-to-cell communication, biofilm formation, virulence enhancement, disease progression, and drug resistance. In contrast, BEVs have been shown to prevent early-stage biofilm, disperse mature biofilm, and reduce virulence characteristics.

Optimization of Protease Treatment Conditions for Chlorella pyrenoidosa Protein Extraction and Investigation of Its Potential as an Alternative Protein Source.

This study aimed to determine enzymes that effectively extract Chlorella pyrenoidosa proteins and optimize the processing conditions using response surface methods. Furthermore, the potential of enzymatically hydrolyzed C. pyrenoidosa protein extract (CPE) as a substitute protein source was investigated. The enzymatic hydrolysis conditions for protein extraction were optimized using single-factor analysis and a response surface methodology-Box-Behnken design. The R2 value of the optimized model was 0.9270, indicating the reliability of the model, and the optimal conditions were as follows: a hydrolysis temperature of 45.56 °C, pH 9.1, and a hydrolysis time of 49.85 min. The amino acid composition of CPE was compared to that of C. pyrenoidosa powder (CP), which was found to have a higher content of essential amino acids (EAA). The electrophoretic profiles of CP and CPE confirmed that CPE has a low molecular weight. Furthermore, CPE showed higher antioxidant activity and phenol content than CP, with ABTS and DPPH radical scavenging abilities of 69.40 ± 1.61% and 19.27 ± 3.16%, respectively. CPE had high EAA content, antioxidant activity, and phenol content, indicating its potential as an alternative protein source. Overall, in this study, we developed an innovative, ecofriendly, and gentle enzymatic hydrolysis strategy for the extraction and refinement of Chlorella proteins.

Alteration of oral microbial biofilms by sweeteners.

There is a growing interest in using sweeteners for taste improvement in the food and drink industry. Sweeteners were found to regulate the formation or dispersal of structural components of microbial biofilms. Dietary sugars may enhance biofilm formation and facilitate the development of antimicrobial resistance, which has become a major health issue worldwide. In contrast, bulk and non-nutritive sweeteners are also beneficial for managing microbial infections. This review discusses the clinical significance of oral biofilms formed upon the administration of nutritive and non-nutritive sweeteners. The underlying mechanism of action of sweeteners in the regulation of mono- or poly-microbial biofilm formation and destruction is comprehensively discussed. Bulk and non-nutritive sweeteners have also been used in conjunction with antimicrobial substances to reduce microbial biofilm formation. Formulations with bulk and non-nutritive sweeteners have been demonstrated to be particularly efficient in this regard. Finally, future perspectives with respect to advancing our understanding of mechanisms underlying biofilm regulation activities of sweeteners are presented as well. Several alternative strategies for the application of bulk sweeteners and non-nutritive sweeteners have been employed to control the biofilm-forming microbial pathogens. Gaining insight into the underlying mechanisms responsible for enhancing or inhibiting biofilm formation and virulence properties by both mono- and poly-microbial species in the presence of the sweetener is crucial for developing a therapeutic agent to manage microbial infections.

Cellular and physiological roles of sigma factors in Vibrio spp.: A comprehensive review.

Vibrio species are motile gram-negative bacteria commonly found in aquatic environments. Vibrio species include pathogenic as well as non-pathogenic strains. Pathogenic Vibrio species have been reported in invertebrates and humans, whereas non-pathogenic strains are involved in symbiotic relationships with their eukaryotic hosts. These bacteria are also able to adapt to fluctuations in temperature, salinity, and pH, in addition to oxidative stress, and osmotic pressure in aquatic ecosystems. Moreover, they have also developed protective mechanisms against the immune systems of their hosts. Vibrio species accomplish adaptation to changing environments outside or inside the host by altering their gene expression profiles. To this end, several sigma factors specifically regulate gene expression, particularly under stressful environmental conditions. Moreover, other sigma factors are associated with biofilm formation and virulence as well. This review discusses different types of sigma and anti-sigma factors of Vibrio species involved in virulence and regulation of gene expression upon changes in environmental conditions. The evolutionary relationships between sigma factors with various physiological roles in Vibrio species are also discussed extensively.

pH-responsive polymeric nanomaterials for the treatment of oral biofilm infections.

Bacterial and fungal pathogens forming oral biofilms present significant public health challenges due to the failure of antimicrobial drugs. The ability of biofilms to lower pH levels results in dental plaque, leading to gingivitis and cavities. Nanoparticles (NPs) have attracted considerable interest for drug delivery and, thus, as a solution to biofilm-related microbial infections. A novel strategy in this regard involves using pH-responsive polymeric NPs within the acidic microenvironment of oral biofilms. The acidity of the oral biofilm microenvironment is governed by carbohydrate metabolism, accumulation of lactic acid, and extracellular DNA of extracellular polymeric substances by oral biofilm-forming microbial pathogens. This acidity also provides an opportunity to enhance antibacterial activity against biofilm cells using pH-responsive drug delivery approaches. Thus, various polymeric NPs loaded with poorly soluble drugs and responsive to the acidic pH of oral biofilms have been developed. This review focuses on various forms of such polymeric NPs loaded with drugs. The fundamental mechanisms of action of pH-responsive polymeric NPs, their cytological toxicity, and in vivo efficacy testing are thoroughly discussed.

Motility of Acinetobacter baumannii: regulatory systems and controlling strategies.

Acinetobacter baumannii is a Gram-negative opportunistic zoonotic pathogenic bacterium that causes nosocomial infections ranging from minor to life-threatening. The clinical importance of this zoonotic pathogen is rapidly increasing due to the development of multiple resistance mechanisms and the synthesis of numerous virulence factors. Although no flagellum-mediated motility exists, it may move through twitching or surface-associated motility. Twitching motility is a coordinated multicellular movement caused by the extension, attachment, and retraction of type IV pili, which are involved in surface adherence and biofilm formation. Surface-associated motility is a kind of movement that does not need appendages and is most likely driven by the release of extra polymeric molecules. This kind of motility is linked to the production of 1,3-diaminopropane, lipooligosaccharide formation, natural competence, and efflux pump proteins. Since A. baumannii's virulence qualities are directly tied to motility, it is possible that its motility may be used as a specialized preventative or therapeutic measure. The current review detailed the signaling mechanism and involvement of various proteins in controlling A. baumannii motility. As a result, we have thoroughly addressed the role of natural and synthetic compounds that impede A. baumannii motility, as well as the underlying action mechanisms. Understanding the regulatory mechanisms behind A. baumannii's motility features will aid in the development of therapeutic drugs to control its infection. KEY POINTS: • Acinetobacter baumannii exhibits multiple resistance mechanisms. • A. baumannii can move owing to twitching and surface-associated motility. • Natural and synthetic compounds can attenuate A. baumannii motility.

Natural and synthetic molecules with potential to enhance biofilm formation and virulence properties in Pseudomonas aeruginosa.

Pseudomonas aeruginosa can efficiently adapt to changing environmental conditions due to its ubiquitous nature, intrinsic/acquired/adaptive resistance mechanisms, high metabolic versatility, and the production of numerous virulence factors. As a result, P. aeruginosa becomes an opportunistic pathogen, causing chronic infection in the lungs and several organs of patients suffering from cystic fibrosis. Biofilm established by P. aeruginosa in host tissues and medical device surfaces has been identified as a major obstruction to antimicrobial therapy. P. aeruginosa is very likely to be closely associated with the various microorganisms in the host tissues or organs in a pathogenic or nonpathogenic behavior. Aside from host-derived molecules, other beneficial and pathogenic microorganisms produce a diverse range of secondary metabolites that either directly or indirectly favor the persistence of P. aeruginosa. Thus, it is critical to understand how P. aeruginosa interacts with different molecules and ions in the host and abiotic environment to produce extracellular polymeric substances and virulence factors. Thus, the current review discusses how various natural and synthetic molecules in the environment induce biofilm formation and the production of multiple virulence factors.

Treatment of Staphylococcus aureus and Candida albicans polymicrobial biofilms by phloroglucinol-gold nanoparticles.

The co-isolation of Staphylococcus aureus and Candida albicans from host tissues and organs and their in vitro and in vivo interaction studies suggest a synergistic relationship in forming polymicrobial biofilms. In particular, during polymicrobial biofilm formation, S. aureus becomes coated in the extracellular matrix secreted by C. albicans, leading to enhanced resistance to antibiotics. Accordingly, understanding the interactions between S. aureus and C. albicans in polymicrobial biofilms is of utmost importance in establishing treatment strategies for polymicrobial infections. As an alternate technique, nanoparticles were used in this investigation to suppress polymicrobial biofilm. The current study aims to manufacture gold nanoparticles (AuNPs) using phloroglucinol (PG), a natural chemical, and test their inhibitory capabilities against S. aureus and C. albicans biofilms in standard and host-mimicking media (like saliva and sputum). PG-AuNPs have a spherical form with an average size of 46.71 ± 6.40 nm. The minimum inhibitory concentration (MIC) values differed when PG-AuNPs were evaluated in the standard and host-mimicking artificial media. The MIC of PG-AuNPs against S. aureus and C. albicans was 2048 µg/mL in both the standard and artificial sputum media. However, the MIC in saliva was only 128 µg/mL. The initial stage polymicrobial biofilm of S. aureus and C. albicans was dramatically decreased at the sub-MIC of PG-AuNPs in both standard and host-mimicking media. S. aureus and C. albicans mature polymicrobial biofilms were more effectively eliminated by MIC and sub-MIC of PG-AuNPs. This study indicates that PG-AuNPs have the ability to limit the formation of polymicrobial biofilms caused by bacterial and fungal diseases.

Functional diversity of c-di-GMP receptors in prokaryotic and eukaryotic systems.

Cyclic bis-(3', 5')-dimeric guanosine monophosphate (c-di-GMP) is ubiquitous in many bacterial species, where it functions as a nucleotide-based secondary messenger and is a vital regulator of numerous biological processes. Due to its ubiquity, most bacterial species possess a wide range of downstream receptors that has a binding affinity to c-di-GMP and elicit output responses. In eukaryotes, several enzymes and riboswitches operate as receptors that interact with c-di-GMP and transduce cellular or environmental signals. This review examines the functional variety of receptors in prokaryotic and eukaryotic systems that exhibit distinct biological responses after interacting with c-di-GMP. Evolutionary relationships and similarities in distance among the c-di-GMP receptors in various bacterial species were evaluated to understand their specificities. Furthermore, residues of receptors involved in c-di-GMP binding are summarized. This review facilitates the understanding of how distinct receptors from different origins bind c-di-GMP equally well, yet fulfill diverse biological roles at the interspecies, intraspecies, and interkingdom levels. Furthermore, it also highlights c-di-GMP receptors as potential therapeutic targets, particularly those found in pathogenic microorganisms. Video Abstract.

Controlling biofilm and virulence properties of Gram-positive bacteria by targeting wall teichoic acid and lipoteichoic acid.

Wall teichoic acid (WTA) and lipoteichoic acid (LTA) are structural components of Gram-positive bacteria's peptidoglycan and cell membrane, which are mostly anionic glycopolymers. WTA confers numerous physiological, virulence, and pathogenic features to bacterial pathogens. It controls cell shape, cell division, and the localisation of autolytic enzymes and ion homeostasis. In the context of virulence and pathogenicity, it aids bacterial cell attachment and colonisation and protects against the host defence system and antibiotics. Having such a broad function in pathogenic bacteria's lifecycle, WTA/LTA become one of the potential targets for antibacterial agents to reduce bacterial infection in the host. The number of reports for targeting the WTA/LTA pathway has risen, mostly by focusing on three distinct targets: antivirulence targets, ß-lactam potentiator targets, and essential targets. The current review looked at the role of WTA/LTA in biofilm development and virulence in a range of Gram-positive pathogenic bacteria. Furthermore, alternate strategies, such as the application of natural and synthetic compounds that target the WTA/LTA pathway, have been thoroughly discussed. Moreover, the application of nanomaterials and a combination of drugs have also been discussed as a viable method for targeting the WTA/LTA in numerous Gram-positive bacteria. In addition, a future perspective for controlling bacterial infection by targeting the WTA/LTA is proposed.

Chitinases as key virulence factors in microbial pathogens: Understanding their role and potential as therapeutic targets.

Chitinases are crucial for the survival of bacterial and fungal pathogens both during host infection and outside the host in the environment. Chitinases facilitate adhesion onto host cells, act as virulence factors during infection, and provide protection from the host immune system, making them crucial factors in the survival of microbial pathogens. Understanding the mechanisms behind chitinase action is beneficial to design novel therapeutics to control microbial infections. This review explores the role of chitinases in the pathogenesis of bacterial, fungal, and viral infections. The mechanisms underlying the action of chitinases of bacterial, fungal, and viral pathogens in host cells are thoroughly reviewed. The evolutionary relationships between chitinases of various bacterial, fungal, and viral pathogens are discussed to determine their involvement in processes, such as adhesion and host immune system modulation. Gaining a better understanding of the distribution and activity of chitinases in these microbial pathogens can help elucidate their role in the invasion and infection of host cells.

Inhibition of Mixed Biofilms of Candida albicans and Staphylococcus aureus by ß-Caryophyllene-Gold Nanoparticles.

Polymicrobial biofilms, consisting of fungal and bacterial pathogens, often contribute to the failure of antimicrobial treatment. The growing resistance of pathogenic polymicrobial biofilms to antibiotics has led to the development of alternative strategies to combat polymicrobial diseases. To this end, nanoparticles synthesized using natural molecules have received significant attention for disease treatment. Here, gold nanoparticles (AuNPs) were synthesized using ß-caryophyllene, a bioactive compound isolated from various plant species. The shape, size, and zeta potential of the synthesized ß-c-AuNPs were found to be non-spherical, 17.6 ± 1.2 nm, and -31.76 ± 0.73 mV, respectively. A mixed biofilm of Candida albicans and Staphylococcus aureus was used to test the efficacy of the synthesized ß-c-AuNPs. The results revealed a concentration-dependent inhibition of the initial stages of formation of single-species as well as mixed biofilms. Furthermore, ß-c-AuNPs also eliminated mature biofilms. Therefore, using ß-c-AuNPs to inhibit biofilm and eradicate bacterial-fungal mixed biofilms represents a promising therapeutic approach for controlling polymicrobial infections.

Pseudomonas aeruginosa virulence attenuation by inhibiting siderophore functions.

Pseudmonas aeruginosa is a Gram-negative bacterium known to be ubiquitous and recognized as one of the leading causes of infections such as respiratory, urinary tract, burns, cystic fibrosis, and in immunocompromised individuals. Failure of antimicrobial therapy has been documented to be attributable due to the development of various resistance mechanisms, with a proclivity to develop additional resistance mechanisms rapidly. P. aeruginosa virulence attenuation is an alternate technique for disrupting pathogenesis without impacting growth. The iron-scavenging siderophores (pyoverdine and pyochelin) generated by P. aeruginosa have various properties like scavenging iron, biofilm formation, quorum sensing, increasing virulence, and toxicity to the host. As a result, developing an antivirulence strategy, specifically inhibiting the P. aeruginosa siderophore, has been a promising therapeutic option to limit their infection. Several natural, synthetic compounds and nanoparticles have been identified as potent inhibitors of siderophore production/biosynthesis, function, and transport system. The current review discussed pyoverdine and pyochelin's synthesis and transport system in P. aeruginosa. Furthermore, it is also focused on the role of several natural and synthetic compounds in reducing P. aeruginosa virulence by inhibiting siderophore synthesis, function, and transport. The underlying mechanism involved in inhibiting the siderophore by natural and synthetic compounds has also been explained. KEY POINTS: • Pseudomonas aeruginosa is an opportunistic pathogen linked to chronic respiratory, urinary tract, and burns infections, as well as cystic fibrosis and immunocompromised patients. • P. aeruginosa produces two virulent siderophores forms: pyoverdine and pyochelin, which help it to survive in iron-deficient environments. • The inhibition of siderophore production, transport, and activity using natural and synthesized drugs has been described as a potential strategy for controlling P. aeruginosa infection.

Multiple potential strategies for the application of nisin and derivatives.

Nisin is a naturally occurring bioactive small peptide produced by Lactococcus lactis subsp. lactis and belongs to the Type A (I) lantibiotics. Due to its potent antimicrobial activity, it has been broadly employed to preserve various food materials as well as to combat a variety of microbial pathogens. The present review discusses the antimicrobial properties of nisin and different types of their derivatives employed to treat microbial pathogens with a detailed underlying mechanism of action. Several alternative strategies such as combination, conjugation, and nanoformulations have been discussed in order to address several issues such as rapid degradation, instability, and reduced activity due to the various environmental factors that arise in the applications of nisin. Furthermore, the evolutionary relationship of many nisin genes from different nisin-producing bacterial species has been investigated. A detailed description of the natural and bioengineered nisin variants, as well as the underlying action mechanisms, has also been provided. The chemistry used to apply nisin in conjugation with natural or synthetic compounds as a synergetic mode of antimicrobial action has also been thoroughly discussed. The current review will be useful in learning about recent and past research that has been performed on nisin and its derivatives as antimicrobial agents.