Antimicrobial peptides: Coming to the end of antibiotic era, the most promising agents

Antimicrobial peptides: has their time arrived?

In recent years the rapid emergence of drug resistant microorganisms has become a major health problem worldwide. The number of multidrug resistant (MDR) bacteria is in a rapid increase. Therefore, there is an urgent need to develop new antimicrobial agent that is active against MDR. Among the possible candidates, antimicrobial peptides (AMPs) represent a promising alternative. Many AMPs candidates were in clinical development and the Nisin was approved in many food products. Exact mechanism of AMPs action has not been fully elucidated. More comprehensive of the mechanism of action provide a path towards overcoming the toxicity limitation. This chapter is a review that provides an overview of bacterial AMPs named bacteriocin, focusing on their diverse mechanism of action. We develop here the structure–function relationship of many AMPs. A good understanding of AMPS structure–function relationship can helps the scientific in the conception of new active AMPs by the evaluation of the role of each residue and the determination of the essential amino acids for activity. This feature helps the development of the second-generation AMPs with high potential antimicrobial activity and more.

As potential alternatives to conventional antibiotics, antimicrobial peptides have attracted great attention in recent years. This review provides an overview of their characteristics and mechanisms of action, summarizes the current progress in clinical research and challenges in clinical utility. Antimicrobial peptides display robust activity against a wide variety of pathogens, including multidrug resistant bacteria, and are less susceptible to resistance development. Dozens of antimicrobial peptides are currently in various stages of clinical trials. However, some intrinsic drawbacks limit their clinical utility: toxicity, stability and manufacturing costs. Researchers have tried to modify the structure of antimicrobial peptides and worked on developing peptidomimetics. It is believed that antimicrobial peptides and peptidomimetics will play an important role against multidrug resistant bacteria in the future. Key words: Dermcidins; Infection; Drug resistance; Clinical Trial; Peptidomimetics

In Gram-negative bacteria, multidrug resistance is a term that is used to describe mechanisms of resistance by chromosomal genes that are activated by induction or mutation caused by the stress of exposure to antibiotics in natural and clinical environments. Unlike plasmid-borne resistance genes, there is no alteration or degradation of drugs or need for genetic transfer. Exposure to a single drug leads to cross-resistance to many other structurally and functionally unrelated drugs. The only mechanism identified for multidrug resistance in bacteria is drug efflux by membrane transporters, even though many of these transporters remain to be identified. The enteric bacteria exhibit mostly complex multidrug resistance systems which are often regulated by operons or regulons. The purpose of this review is to survey molecular mechanisms of multidrug resistance in enteric and other Gram-negative bacteria, and to speculate on the origins and natural physiological functions of the genes involved.

In Gram-negative bacteria, multidrug resistance is a term that is used to describe mechanisms of resistance by chromosomal genes that are activated by induction or mutation caused by the stress of exposure to antibiotics in natural and clinical environments. Unlike plasmid-borne resistance genes, there is no alteration or degradation of drugs or need for genetic transfer. Exposure to a single drug leads to cross-resistance to many other structurally and functionally unrelated drugs. The only mechanism identified for multidrug resistance in bacteria is drug efflux by membrane transporters, even though many of these transporters remain to be identified. The enteric bacteria exhibit mostly complex multidrug resistance systems which are often regulated by operons or regulons. The purpose of this review is to survey molecular mechanisms of multidrug resistance in enteric and other Gram-negative bacteria, and to speculate on the origins and natural physiological functions of the genes involved.

Augmentation of the antibacterial activities of Pt5-derived antimicrobial peptides (AMPs) by amino acid substitutions: Design of novel AMPs against MDR bacteria

Current research in the field of antimicrobials is focused on developing novel antimicrobial agents to counteract the huge dilemma that the human population is mainly facing in regards to the rise of bacterial resistance and biofilm infections. Host defense peptides (HDPs) are a promising group of molecules for antimicrobial development as they display several attractive features suitable for antimicrobial activity, including their broad spectrum of activity and potency against bacteria. AamAP1 is a novel HDP that belongs to the venom of the North African scorpion Androctonus amoeruxi. In vitro antimicrobial assays revealed that the peptide displays moderate activity against Gram-positive and Gram-negative bacteria. Additionally, the peptide proved to be highly hemolytic and displayed significantly high toxicity against mammalian cells. In our study, a novel synthetic peptide analogue named A3 was synthetically modified from AamAP1 in order to enhance its activity and toxicity profile. The design strategy depended on modifying the amino acid sequence of AamAP1 in order to alter its net positive charge, percentage helicity and modify other parameters that are involved theoretically in HDPs activity. Accordingly, A3 was evaluated for its in vitro antimicrobial and anti-biofilm activity individually and in combination with four different types of conventional antibiotics against clinical isolates of multi-drug resistant (MDR) Gram-positive bacteria. A3 was also evaluated for its cytotoxicity against mammalian cells. A3 managed to selectively inhibit the growth of a wide range of resistant strains of Gram-positive bacteria. Our results also showed that combining A3 with conventional antibiotics caused a synergistic antimicrobial behavior that resulted in decreasing the MIC value for A3 peptide as low as 0.125 µM. At the concentrations needed to inhibit bacterial growth, A3 displayed minimal mammalian cell toxicity. In conclusion, A3 exhibits enhanced activity and selectivity when compared with the parent natural scorpion venom peptide. The combination of A3 with conventional antibiotics could provide researchers in the antimicrobial drug development field with a potential alternative for conventional antibiotics against MDR bacteria.

The United Nations have committed to end the epidemics of communicable diseases by 2030 (SDG Target 3.3). In contrast with this ambition, the rise of Multi Drug Resistant (MDR) and Pan Drug Resistant (PDR) bacteria poses a threat of a return to the pre-antibiotic era. It is of high priority to find new therapies that target the ESKAPEE group of pathogens and their drug-resistant strains. Antimicrobial peptides (AMPs) are an emerging class of antibiotics that hold promises of overcoming bacterial resistance by using both novel mechanisms of action as well as targeting already known pathways. The chemical space of AMPs is potentially huge and methodologies allowing the rational exploration of novel structures are highly needed. This review focuses on case studies that give novel insights about the mechanisms of action, resistance and selectivity of some relevant AMPs, exemplifying the importance of microscopic, computational and experimental tools. Particular focus will be devoted to bacterial membranes and how AMPs can target them while sparing human plasma membranes, in order to become safer drugs. The lessons learned from the literature cases give directions toward the development of AMPs as drug products.

Facial amphiphilic naphthoic acid-derived antimicrobial polymers against multi-drug resistant gram-negative bacteria and biofilms

Multidrug-resistant (MDR) bacteria are becoming more and more common, which presents a serious threat to world health and could eventually render many of the antibiotics we currently use useless. The research and development of innovative antimicrobial tactics that can defeat these hardy infections are imperative in light of this predicament. Antimicrobial peptides (AMPs), which have attracted a lot of attention due to their distinct modes of action and capacity to elude conventional resistance mechanisms, are among the most promising of these tactics. As a promising substitute for conventional antibiotics, AMPs are a varied class of naturally occurring compounds that target bacteria membranes and disrupt cellular activities to demonstrate broad-spectrum antimicrobial activity. The objective of this study is to present a thorough summary of the current knowledge regarding AMP mechanisms against MDR bacteria, including immunological modulation, interactions with microbial membranes, and possible synergy with currently used antimicrobial drugs. In addition, we define the review's scope to include the most recent developments in AMP research, emphasizing the innovations' development, optimization, and therapeutic promise. We hope to emphasize the crucial role that AMPs will play in the future of antimicrobial therapy by bringing together recent research and highlighting current issues. We also hope to advocate for AMPs' continued research and development as part of a comprehensive strategy to counteract the growing threat of antibiotic resistance.

Cathelicidin antimicrobial peptide from Alligator mississippiensis has antibacterial activity against multi-drug resistant Acinetobacter baumanii and Klebsiella pneumoniae

Antimicrobial peptide (AMP), also called host defense peptide, is a part of the innate immune system in eukaryotic organisms. AMPs are also produced by prokaryotes in response to stressful conditions and environmental changes. They have a broad spectrum of activity against both Gram positive and Gram negative bacteria. They are also effective against viruses, fungi, parasites, and cancer cells. AMPs are cationic or amphipathic in nature, but in recent years cationic AMPs have attracted a lot of attention because cationic AMPs can easily interact with negatively charged bacterial and cancer cell membranes through electrostatic interaction. AMPs can also eradicate bacterial biofilms and have broad-spectrum activity against multidrug resistant (MDR) bacteria. Although the main target site for AMPs is the cell membrane, they can also disrupt bacterial cell walls, interfere with protein folding and inhibit enzymatic activity. In recent centuries antibiotics are gradually losing their potential because of the continuous rise of antibiotic resistant bacteria. Therefore, there is an urgent need to develop novel therapeutic approaches to treat MDR bacteria, and AMP is such an alternative treatment option over conventional antibiotics. Several communicable diseases like tuberculosis and non-communicable diseases such as cancer can be treated by using AMPs. One of the major advantages of using AMP is that it works with high specificity and does not cause any harm to normal tissue. AMPs can be modified to improve their efficacy. In this narrative review, we are focusing on the potential application of AMPs in medical science.

The emergence and dissemination of multidrug resistant (MDR) bacteria are major challenges for antimicrobial chemotherapy of bacterial infections. In this critical condition, cationic antimicrobial peptides are 'novel' promising candidate antibiotics to overcome the issue. In this study, we investigated the antibacterial mechanism of new melittin-derived peptides (i.e., MDP1 and MDP2) against multidrug resistant Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. MDP1 was designed with deletion of three amino acid residues, i.e., S18, W19, and I20, from the end of second hydrophobic motif of melittin. In the next step, VLTTG in MDP1 sequence was substituted with tryptophan residue. MDP1 and MDP2 had a high-antibacterial activity against MDR and reference strains of S. aureus, E. coli, and P. aeruginosa. DNA and calcein release and flow cytometry assays indicate a time-dependent antibacterial activity on the examined bacteria affected by both MDP1 and MDP2. Finally, SEM analyses highlighted dose- and time-dependent effects of MDP1 and MDP2 on S. aureus and E. coli bacteria by induction of vesicle or pore formation as well as cell lysis. In this study we successfully showed that rational truncation of large hydrophobic motifs can lead to significant reduction in toxicity against human RBCs and improving the antibacterial activity as well. Analyses of data from DNA release, fluorometry, flow cytometry, and morphological assays demonstrated that the MDP1 and MDP2 altered the integrity of both Gram-positive and Gram-negative bacterial membranes and killed the bacteria via membrane damages.

Dealing with MDR bacteria and biofilm in the post-antibiotic era: Application of antimicrobial peptides-based nano-formulation

Rectal Swabs for Detecting Multidrug Resistant Bacteria Prior to Transrectal Prostate Fusion Biopsy: A Prospective Evaluation of Risk Factor Screening and Microbiologic Findings