Non-Lytic Antibacterial Peptides That Translocate Through Bacterial Membranes to Act on Intracellular Targets (original) (raw)
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Antimicrobial peptides: to membranes and beyond
Expert Opinion on Drug Discovery, 2009
Objective: This review will summarize findings on these alternative non-lytic modes of antimicrobial action that go beyond membrane disruption, with an emphasis on the specific interaction with microbial cell wall/membrane components, signaling of AMP exposure, and intracellular targets of peptide action. We will also explore how novel technologies can help to reveal, characterize and exploit these antimicrobial properties. Conclusion: Detailed knowledge on non-lytic modes of action of antimicrobial peptides will help in the design and discovery of novel antibacterial and antifungal compounds.
Beyond membrane-lytic: Intracellular Targeting Mechanisms by Antimicrobial Peptides
Antimicrobial agents and chemotherapy, 2017
Antimicrobial peptides (AMPs) are expressed in various living organisms as first line host defense against potential harmful encounters in the surroundings. AMPs are short polycationic peptides exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of bacterial cell membrane and cell wall. In addition, a number of AMPs form transmembrane channel in the membrane by self-aggregation or polymerization leading to cytoplasm leakage and cell death. However, increasing body of evidences demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs which include nucleic acids and protein biosyntheses, protein folding, proteases, cell division, cell wall biosynthesis, and lipopolysaccharides inhibition. ...
Walking the fine line between intracellular and membrane activities of antibacterial peptides
Letters in Peptide Science, 2003
Analogs of pyrrhocoricin, a proline-rich antibacterial peptide with a potential therapeutic use, show multiple actions on bacterial cells. We used a dual-fluorochrome membrane viability assay to provide evidence that the lead drug candidate, Pip-pyrr-MeArg dimer derivative, kills bacteria better than the native peptide due to an improved activity on bacterial membranes. This assay was also instrumental in documenting that activity on bacterial membranes and toxicity to human cells can be correlated, and the predominant mode of action can be changed from intracellular DnaK inhibition to membrane disintegration. Similar analyses with an alanine-scan on pyrrhocoricin identified Lys3 as a crucial player to interaction with bacterial membranes, three prolines in mid-chain position as being responsible for maintaining structural integrity and Asp2, Tyr6, Leu7, and Arg9 as putative contact points to the D-E helix of the bacterial target protein DnaK.
Focal Targeting of the Bacterial Envelope by Antimicrobial Peptides
Antimicrobial peptides (AMPs) are utilized by both eukaryotic and prokaryotic organisms. AMPs such as the human beta defensins, human neutrophil peptides, human cathelicidin, and many bacterial bacteriocins are cationic and capable of binding to anionic regions of the bacterial surface. Cationic AMPs (CAMPs) target anionic lipids [e.g., phosphatidylglycerol (PG) and cardiolipins (CL)] in the cell membrane and anionic components [e.g., lipopolysaccharide (LPS) and lipoteichoic acid (LTA)] of the cell envelope. Bacteria have evolved mechanisms to modify these same targets in order to resist CAMP killing, e.g., lysinylation of PG to yield cationic lysyl-PG and alanylation of LTA. Since CAMPs offer a promising therapeutic alternative to conventional antibiotics, which are becoming less effective due to rapidly emerging antibiotic resistance, there is a strong need to improve our understanding about the AMP mechanism of action. Recent literature suggests that AMPs often interact with the bacterial cell envelope at discrete foci. Here we review recent AMP literature, with an emphasis on focal interactions with bacteria, including (1) CAMP disruption mechanisms, (2) delocalization of membrane proteins and lipids by CAMPs, and (3) CAMP sensing systems and resistance mechanisms. We conclude with new approaches for studying the bacterial membrane, e.g., lipidomics, high resolution imaging, and non-detergent-based membrane domain extraction.
Antimicrobial peptides as potential anti-biofilm agents against multidrug- resistant bacteria
Bacterial resistance to commonly used drugs has become a global health problem, causing increased infection cases and mortality rate. One of the main virulence determinants in many bacterial infections is biofilm formation, which significantly increases bacterial resistance to antibiotics and innate host defence. In the search to address the chronic infections caused by biofilms, antimicrobial peptides (AMP) have been considered as potential alternative agents to conventional antibiotics. Although AMPs are commonly considered as the primitive mechanism of immunity and has been extensively studied in insects and non-vertebrate organisms, there is now increasing evidence that AMPs also play a crucial role in human immunity. AMPs have exhibited broad-spectrum activity against many strains of Gram-positive and Gram-negative bacteria, including drug-resistant strains, and fungi. In addition, AMPs also showed synergy with classical antibiotics , neutralize toxins and are active in animal models. In this review, the important mechanisms of action and potential of AMPs in the eradication of biofilm formation in multidrug-resistant pathogen, with the goal of designing novel antimicrobial therapeutics, are discussed.
Antimicrobial Peptides as an Opportunity Against Bacterial Diseases
Current Medicinal Chemistry, 2015
Antimicrobial peptides (AMPs) are an heterogeneous group of small amino acidic molecules produced by the innate immune system of a variety of organisms encompassing all orders of life from eukaryotes to amphibians, insects and plants. Numerous AMPs have been isolated from natural sources and many others have been de novo designed and synthetically produced. AMPs have antimicrobial activity in the micromolar range and compared with traditional antibiotics, they kill bacteria very rapidly. They act, principally, by the electrostatic attraction to negatively charged bacterial cells and consequently membrane disruption, but their antibacterial activity may also involve interference with metabolic processes or different cytoplasmic targets. AMPs are a group of unique and incredible compounds that may be directed to a therapeutic use either alone or in combination with existing antibiotics.
Interactions of Antimicrobial Peptides with Bacterial Membranes and Membrane Components
Antimicrobial peptides (AMPs) have attracted considerable recent interest as potential therapeutics, motivated by increasing resistance development against conventional antibiotics. This brief overview summarizes some key aspects related to the interaction of AMPs with bacterial and cell membranes, as well as with membrane components, which is at the core of the mode-of-action of these compounds. Throughout, studies on peptide interactions with model lipid membranes and membrane components are correlated to biological results on antimicrobial and anti-inflammatory effects of AMPs, and translated into therapeutic considerations.
Antimicrobial and Antibiofilm Peptides
Biomolecules, 2020
The increasing onset of multidrug-resistant bacteria has propelled microbiology research towards antimicrobial peptides as new possible antibiotics from natural sources. Antimicrobial peptides are short peptides endowed with a broad range of activity against both Gram-positive and Gram-negative bacteria and are less prone to trigger resistance. Besides their activity against planktonic bacteria, many antimicrobial peptides also show antibiofilm activity. Biofilms are ubiquitous in nature, having the ability to adhere to virtually any surface, either biotic or abiotic, including medical devices, causing chronic infections that are difficult to eradicate. The biofilm matrix protects bacteria from hostile environments, thus contributing to the bacterial resistance to antimicrobial agents. Biofilms are very difficult to treat, with options restricted to the use of large doses of antibiotics or the removal of the infected device. Antimicrobial peptides could represent good candidates to ...
Frontiers in chemistry, 2018
Antimicrobial peptides (AMPs) are promising novel antibiotics since they have shown antimicrobial activity against a wide range of bacterial species, including multiresistant bacteria; however, toxicity is the major barrier to convert antimicrobial peptides into active drugs. A profound and proper understanding of the complex interactions between these peptides and biological membranes using biophysical tools and model membranes seems to be a key factor in the race to develop a suitable antimicrobial peptide therapy for clinical use. In the search for such therapy, different combined approaches with conventional antibiotics have been evaluated in recent years and demonstrated to improve the therapeutic potential of AMPs. Some of these approaches have revealed promising additive or synergistic activity between AMPs and chemical antibiotics. This review will give an insight into the possibilities that physicochemical tools can give in the AMPs research and also address the state of th...