Antimicrobial peptides and bacteriocins: alternatives to traditional antibiotics

AbstractAntimicrobial peptides (AMPs) are ubiquitous, gene-encoded natural antibiotics that have gained recent attention in the search for new antimicrobials to combat infectious disease. In multicellular organisms, AMPs, such as defensins and cathelicidins, provide a coordinated protective response against infection and are a principal component of innate immunity in vertebrates. In unicellular organisms, AMPs, such as bacteriocins, function to suppress competitor species. Because many AMPs kill bacteria by disruption of membrane integrity and are thus thought to be less likely to induce resistance, AMPs are being extensively evaluated as novel antimicrobial drugs. This review summarizes and discusses the antibiotic properties of AMPs highlighting their potential as alternatives to conventional antibiotics.

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Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

Current Medicinal Chemistry ◽

10.2174/0929867325666180117142142 ◽

2018 ◽

Vol 25 (21) ◽

pp. 2503-2519 ◽

Cited By ~ 4

Author(s):

Anne Kokel ◽

Marianna Torok

Keyword(s):

Side Effects ◽

Antimicrobial Peptides ◽

Potential Drug ◽

Green Technologies ◽

Specific Antibodies ◽

Structural Modifications ◽

Drug Candidates ◽

Induce Resistance ◽

Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

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Antimicrobial peptides of the genus Bacillus: a new era for antibiotics

Canadian Journal of Microbiology ◽

10.1139/cjm-2014-0613 ◽

2015 ◽

Vol 61 (2) ◽

pp. 93-103 ◽

Cited By ~ 113

Author(s):

Chandra Datta Sumi ◽

Byung Wook Yang ◽

In-Cheol Yeo ◽

Young Tae Hahm

Keyword(s):

Antimicrobial Peptides ◽

Well Being ◽

Rapid Onset ◽

Antibacterial Drug ◽

Genus Bacillus ◽

Antimicrobial Drugs ◽

Food Preservatives ◽

New Era ◽

Peptide Biosynthesis ◽

Conventional Antibiotics

The rapid onset of resistance reduces the efficacy of most conventional antimicrobial drugs and is a general cause of concern for human well-being. Thus, there is great demand for a continuous supply of novel antibiotics to combat this problem. Bacteria-derived antimicrobial peptides (AMPs) have long been used as food preservatives; moreover, prior to the development of conventional antibiotics, these AMPs served as an efficient source of antibiotics. Recently, peptides produced by members of the genus Bacillus were shown to have a broad spectrum of antimicrobial activity against pathogenic microbes. Bacillus-derived AMPs can be synthesized both ribosomally and nonribosomally and can be classified according to peptide biosynthesis, structure, and molecular weight. The precise mechanism of action of these AMPs is not yet clear; however, one proposed mechanism is that these AMPs kill bacteria by forming channels in and (or) disrupting the bacterial cell wall. Bacillus-derived AMPs have potential in the pharmaceutical industry, as well as the food and agricultural sectors. Here, we focus on Bacillus-derived AMPs as a novel alternative approach to antibacterial drug development. We also provide an overview of the biosynthesis, mechanisms of action, applications, and effectiveness of different AMPs produced by members of the Bacillus genus, including several recently identified novel AMPs.

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Activity of Antimicrobial Peptides and Ciprofloxacin against Pseudomonas aeruginosa Biofilms

Molecules ◽

10.3390/molecules25173843 ◽

2020 ◽

Vol 25 (17) ◽

pp. 3843

Author(s):

Muhammad Yasir ◽

Debarun Dutta ◽

Mark D.P. Willcox

Keyword(s):

Pseudomonas Aeruginosa ◽

Minimum Inhibitory Concentration ◽

Confocal Microscopy ◽

Antimicrobial Peptides ◽

Biofilm Formation ◽

Inhibitory Concentration ◽

Development Of Resistance ◽

Induce Resistance ◽

Additional Resistance ◽

Conventional Antibiotics

Pseudomonas aeruginosa is increasingly resistant to conventional antibiotics, which can be compounded by the formation of biofilms on surfaces conferring additional resistance. P. aeruginosa was grown in sub-inhibitory concentrations of the antimicrobial peptides (AMPs) melimine and Mel4 or ciprofloxacin for 30 consecutive days to induce the development of resistance. Antibiofilm effect of AMPs and ciprofloxacin was evaluated using crystal violet and live/dead staining with confocal microscopy. Effect on the cell membrane of biofilm cells was evaluated using DiSC(3)-5 dye and release of intracellular ATP and DNA/RNA. The minimum inhibitory concentration (MIC) of ciprofloxacin increased 64-fold after 30 passages, but did not increase for melimine or Mel4. Ciprofloxacin could not inhibit biofilm formation of resistant cells at 4× MIC, but both AMPs reduced biofilms by >75% at 1× MIC. At 1× MIC, only the combination of either AMP with ciprofloxacin was able to significantly disrupt pre-formed biofilms (≥61%; p < 0.001). Only AMPs depolarized the cell membranes of biofilm cells at 1× MIC. At 1× MIC either AMP with ciprofloxacin released a significant amount of ATP (p < 0.04), but did not release DNA/RNA. AMPs do not easily induce resistance in P. aeruginosa and can be used in combination with ciprofloxacin to treat biofilm.

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Antimicrobial peptides: Application informed by evolution

Science ◽

10.1126/science.aau5480 ◽

2020 ◽

Vol 368 (6490) ◽

pp. eaau5480 ◽

Cited By ~ 44

Author(s):

Brian P. Lazzaro ◽

Michael Zasloff ◽

Jens Rolff

Keyword(s):

Population Genetics ◽

Antimicrobial Peptides ◽

High Capacity ◽

Essential Components ◽

Evolution Of Resistance ◽

Spectrum Activity ◽

Conventional Antibiotics ◽

Multicellular Organisms ◽

Collateral Harm ◽

Broad Spectrum Activity

Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have been classically assumed to have broad-spectrum activity and simple kinetics, but recent evidence suggests an unexpected degree of specificity and a high capacity for synergies. Deeper evaluation of the molecular evolution and population genetics of AMP genes reveals more evidence for adaptive maintenance of polymorphism in AMP genes than has previously been appreciated, as well as adaptive loss of AMP activity. AMPs exhibit pharmacodynamic properties that reduce the evolution of resistance in target microbes, and AMPs may synergize with one another and with conventional antibiotics. Both of these properties make AMPs attractive for translational applications. However, if AMPs are to be used clinically, it is crucial to understand their natural biology in order to lessen the risk of collateral harm and avoid the crisis of resistance now facing conventional antibiotics.

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Antimicrobial Peptides: A Promising Avenue for Human Healthcare

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666191011121722 ◽

2020 ◽

Vol 21 (2) ◽

pp. 90-96 ◽

Cited By ~ 2

Author(s):

Girish M. Bhopale

Keyword(s):

Antimicrobial Peptides ◽

Antimicrobial Peptide ◽

Antimicrobial Agents ◽

Current Status ◽

Antimicrobial Drugs ◽

Spectrum Activity ◽

Low Levels ◽

Human Healthcare ◽

Broad Spectrum Activity ◽

Promising Avenue

Antimicrobial drugs resistant microbes have been observed worldwide and therefore alternative development of antimicrobial peptides has gained interest in human healthcare. Enormous progress has been made in the development of antimicrobial peptide during the last decade due to major advantages of AMPs such as broad-spectrum activity and low levels of induced resistance over the current antimicrobial agents. This review briefly provides various categories of AMP, their physicochemical properties and mechanism of action which governs their penetration into microbial cell. Further, the recent information on current status of antimicrobial peptide development, their applications and perspective in human healthcare are also described.

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Antimicrobial Peptides and their Multiple Effects at Sub-Inhibitory Concentrations

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200427090912 ◽

2020 ◽

Vol 20 (14) ◽

pp. 1264-1273 ◽

Cited By ~ 1

Author(s):

Bruno Casciaro ◽

Floriana Cappiello ◽

Walter Verrusio ◽

Mauro Cacciafesta ◽

Maria Luisa Mangoni

Keyword(s):

Antimicrobial Peptides ◽

Inhibitory Concentration ◽

Multidrug Resistant ◽

Mechanisms Of Action ◽

New Drugs ◽

Lead Compounds ◽

Bacterial Pathogenicity ◽

Growth Inhibitory ◽

Resistant Strains ◽

Conventional Antibiotics

The frequent occurrence of multidrug-resistant strains to conventional antimicrobials has led to a clear decline in antibiotic therapies. Therefore, new molecules with different mechanisms of action are extremely necessary. Due to their unique properties, antimicrobial peptides (AMPs) represent a valid alternative to conventional antibiotics and many of them have been characterized for their activity and cytotoxicity. However, the effects that these peptides cause at concentrations below the minimum growth inhibitory concentration (MIC) have yet to be fully analyzed along with the underlying molecular mechanism. In this mini-review, the ability of AMPs to synergize with different antibiotic classes or different natural compounds is examined. Furthermore, data on microbial resistance induction are reported to highlight the importance of antibiotic resistance in the fight against infections. Finally, the effects that sub-MIC levels of AMPs can have on the bacterial pathogenicity are summarized while showing how signaling pathways can be valid therapeutic targets for the treatment of infectious diseases. All these aspects support the high potential of AMPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities.

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Freezing

10.1093/oso/9780199551668.003.0006 ◽

2017 ◽

Author(s):

Andrew Clarke

Keyword(s):

Thermal Hysteresis ◽

Higher Plants ◽

Terrestrial Environment ◽

Cold Temperatures ◽

Cellular Dehydration ◽

A Cell ◽

Unicellular Organisms ◽

Cell Cytosol ◽

Freezing Temperatures ◽

Multicellular Organisms

Freezing is a widespread ecological challenge, affecting organisms in over half the terrestrial environment as well as both polar seas. With very few exceptions, if a cell freezes internally, it dies. Polar teleost fish in shallow waters avoid freezing by synthesising a range of protein or glycoprotein antifreezes. Terrestrial organisms are faced with a far greater thermal challenge, and exhibit a more complex array of responses. Unicellular organisms survive freezing temperatures by preventing ice nucleating within the cytosol, and tolerating the cellular dehydration and membrane disruption that follows from ice forming in the external environment. Multicellular organisms survive freezing temperatures by manipulating the composition of the extracellular body fluids. Terrestrial organisms may freeze at high subzero temperatures, often promoted by ice nucleating proteins, and small molecular mass cryoprotectants (often sugars and polyols) moderate the osmotic stress on cells. A range of chaperone proteins (dehydrins, LEA proteins) help maintain the integrity of membranes and macromolecules. Thermal hysteresis (antifreeze) proteins prevent damaging recrystallisation of ice. In some cases arthropods and higher plants prevent freezing in their extracellular fluids and survive by supercooling. Vitrification of extracellular water, or of the cell cytosol, may be a more widespread response to very cold temperatures than recognised to date.

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Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties

International Journal of Molecular Sciences ◽

10.3390/ijms22115617 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5617

Author(s):

Martin Vestergaard ◽

Bolette Skive ◽

Ilona Domraceva ◽

Hanne Ingmer ◽

Henrik Franzyk

Keyword(s):

Membrane Integrity ◽

Bactericidal Effect ◽

Structural Features ◽

Intrinsic Resistance ◽

Minimal Inhibitory Concentrations ◽

Ic50 Values ◽

Assay Time ◽

Vancomycin Resistant ◽

Conventional Antibiotics ◽

Time Kill

Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide/β-peptoid hybrids were found to have antibacterial activity against eight E. faecium and E. faecalis isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time–kill studies, as well as assessment of membrane integrity. E. faecium isolates proved more susceptible than E. faecalis isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible E. faecium isolates were observed. A test of three peptidomimetics (Ac-[hArg-βNsce]6-NH2, Ac-[hArg-βNsce-Lys-βNspe]3-NH2 and Oct-[Lys-βNspe]6-NH2) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-βNsce-Lys-βNspe]3-NH2 and Oct-[Lys-βNspe]6-NH2 with low MIC values (in the ranges 2–8 µg/mL and 4–16 µg/mL against E. faecium and E. faecalis, respectively) and displaying weak cytotoxic properties (i.e., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC50 values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies.

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