Challenge in the Discovery of New Drugs: Antimicrobial Peptides against WHO-List of Critical and High-Priority Bacteria

Bacterial resistance has intensified in recent years due to the uncontrolled use of conventional drugs, and new bacterial strains with multiple resistance have been reported. This problem may be solved by using antimicrobial peptides (AMPs), which fulfill their bactericidal activity without developing much bacterial resistance. The rapid interaction between AMPs and the bacterial cell membrane means that the bacteria cannot easily develop resistance mechanisms. In addition, various drugs for clinical use have lost their effect as a conventional treatment; however, the synergistic effect of AMPs with these drugs would help to reactivate and enhance antimicrobial activity. Their efficiency against multi-resistant and extensively resistant bacteria has positioned them as promising molecules to replace or improve conventional drugs. In this review, we examined the importance of antimicrobial peptides and their successful activity against critical and high-priority bacteria published in the WHO list.

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Antimicrobial Peptides: An Approach to Combat Resilient Infections

Current Drug Discovery Technologies ◽

10.2174/1570163816666190620114338 ◽

2020 ◽

Vol 17 (4) ◽

pp. 542-552 ◽

Cited By ~ 2

Author(s):

Debaprasad Parai ◽

Pia Dey ◽

Samir K. Mukherjee

Keyword(s):

Antimicrobial Peptides ◽

Developmental Stages ◽

Rapid Development ◽

Resistance Mechanisms ◽

New Drugs ◽

Bacterial Strains ◽

Common People ◽

Wide Range ◽

Microbial Infections ◽

Living Organisms

Background:It was apparent by the end of 1980s that the success against the threats of bacterial pathogens on public health was an illusion, with the rapid development of resistant strains more than the discovery of new drugs. As a consequence, the remedial services were in the backfoot position of being on the losing side of this never-ending evolutionary war. The quest for new antibiotics to overcome resistance problems has long been a top research priority for the researchers and the pharmaceutical industry. However, the resistance problems remain unresolved due to the abrupt misuse of antibiotics by common people, which has immensely worsened the scenario by disseminating antibiotic-resistant bacterial strains around the world.Objective:Thus, immediate action is needed to measure emerging and re-emerging microbial diseases having new resistance mechanisms and to manage their rapid spread among the common public by means of novel alternative metabolites.Conclusion:Antimicrobial Peptides (AMPs) are short, cationic peptides evolved in a wide range of living organisms and serve as the essential part of the host innate immunity. For humans, these effector molecules either can directly kill the foreign microbes or modulate the host immune systems so that the human body could develop some resistance against the microbial infections. In this review, we discuss their history, structural classifications, modes of action, and explain their biological roles as anti-infective agents. We also scrutinize their clinical potentiality, current limitations in various developmental stages and strategies to overcome for their successful clinical applications.

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Combating bacterial resistance by combination of antibiotics with antimicrobial peptides

Pure and Applied Chemistry ◽

10.1515/pac-2018-0707 ◽

2019 ◽

Vol 91 (2) ◽

pp. 199-209 ◽

Cited By ~ 8

Author(s):

Dean E. Sheard ◽

Neil M. O’Brien-Simpson ◽

John D. Wade ◽

Frances Separovic

Keyword(s):

Antimicrobial Peptides ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Synergistic Effects ◽

Resistance Mechanisms ◽

Bacterial Strains ◽

Diverse Range ◽

Recent Emergence ◽

Agricultural Industries ◽

Conventional Antibiotics

Abstract The overuse of antibiotics in the healthcare and agricultural industries has led to the worldwide spread of bacterial resistance. The recent emergence of multidrug resistant (MDR) bacteria has resulted in a call for the development of novel strategies to address this global issue. Research on a diverse range of antimicrobial peptides (AMPs) has shown promising activity against several resistant strains. Increased understanding of the mode of action of AMPs has shown similarity and complementarity to conventional antibiotics and the combination of both has led to synergistic effects in some cases. Combination therapy has been widely used to combat MDR bacterial infections and the recent focus on their application with AMPs may allow antibiotics to be effective against resistant bacterial strains. By conjugation of an antibiotic onto an AMP, a compound may be produced with possibly greater activity and with reduced side-effects and toxicity. The AMP in these conjugates may also act as a unique adjuvant for the antibiotic by disrupting the resistance mechanisms used by bacteria thus allowing the antibiotic to once again be effective. This mini-review outlines some of the current and past work in combining AMPs with conventional antibiotics as strategies to address bacterial resistance.

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The Lactococcal dgkB (yecE) and dxsA Genes for Lipid Metabolism Are Involved in the Resistance to Cell Envelope-Acting Antimicrobials

International Journal of Molecular Sciences ◽

10.3390/ijms22031014 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1014

Author(s):

Aleksandra Tymoszewska ◽

Tamara Aleksandrzak-Piekarczyk

Keyword(s):

Antimicrobial Peptides ◽

Bacterial Resistance ◽

Antimicrobial Agents ◽

Cytoplasmic Membrane ◽

Cross Resistance ◽

Resistant Bacteria ◽

Membrane Targeting ◽

Nucleotide Polymorphisms ◽

Next Generation ◽

Lipid Ii

The emergence of antibiotic-resistant bacteria led to an urgent need for next-generation antimicrobial agents with novel mechanisms of action. The use of positively charged antimicrobial peptides that target cytoplasmic membrane is an especially promising strategy since essential functions and the conserved structure of the membrane hinder the development of bacterial resistance. Aureocin A53- and enterocin L50-like bacteriocins are highly cationic, membrane-targeting antimicrobial peptides that have potential as next-generation antibiotics. However, the mechanisms of resistance to these bacteriocins and cross-resistance against antibiotics must be examined before application to ensure their safe use. Here, in the model bacterium Lactococcus lactis, we studied the development of resistance to selected aureocin A53- and enterocin L50-like bacteriocins and its correlation with antibiotics. First, to generate spontaneous resistant mutants, L.lactis was exposed to bacteriocin BHT-B. Sequencing of their genomes revealed single nucleotide polymorphisms (SNPs) in the dgkB (yecE) and dxsA genes encoding diacylglycerol kinase and 1-deoxy-D-xylulose 5-phosphate synthase, respectively. Then, selected mutants underwent susceptibility tests with a wide array of bacteriocins and antibiotics. The highest alterations in the sensitivity of studied mutants were seen in the presence of cytoplasmic membrane targeting bacteriocins (K411, Ent7, EntL50, WelM, SalC, nisin) and antibiotics (daptomycin and gramicidin) as well as lipid II cycle-blocking bacteriocins (nisin and Lcn972) and antibiotics (bacitracin). Interestingly, decreased via the SNPs accumulation sensitivity to membrane-active bacteriocins and antibiotics resulted in the concurrently increased vulnerability to bacitracin, carbenicillin, or chlortetracycline. It is suspected that SNPs may result in alterations to the efficiency of the nascent enzymes rather than a total loss of their function as neither deletion nor overexpression of dxsA restored the phenotype observed in spontaneous mutants.

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Antimicrobial and Antibiofilm Peptides

Biomolecules ◽

10.3390/biom10040652 ◽

2020 ◽

Vol 10 (4) ◽

pp. 652 ◽

Cited By ~ 12

Author(s):

Angela Di Somma ◽

Antonio Moretta ◽

Carolina Canè ◽

Arianna Cirillo ◽

Angela Duilio

Keyword(s):

Antimicrobial Peptides ◽

Biofilm Formation ◽

Bacterial Resistance ◽

Antimicrobial Agents ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Antibiofilm Activity ◽

Chronic Infections ◽

Planktonic Bacteria ◽

Hostile Environments

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 develop new antibiofilm drugs as they can act at different stages of biofilm formation, on disparate molecular targets and with various mechanisms of action. These include inhibition of biofilm formation and adhesion, downregulation of quorum sensing factors, and disruption of the pre-formed biofilm. This review focuses on the proprieties of antimicrobial and antibiofilm peptides, with a particular emphasis on their mechanism of action, reporting several examples of peptides that over time have been shown to have activity against biofilm.

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Drug Resistance and Gene Transfer Mechanisms in Respiratory/Oral Bacteria

Journal of Dental Research ◽

10.1177/0022034518782659 ◽

2018 ◽

Vol 97 (10) ◽

pp. 1092-1099 ◽

Cited By ~ 7

Author(s):

S. Jiang ◽

J. Zeng ◽

X. Zhou ◽

Y. Li

Keyword(s):

Antibiotic Resistance ◽

Gene Transfer ◽

Nucleic Acids ◽

Bacterial Resistance ◽

Defense Mechanism ◽

Oral Bacteria ◽

New Drugs ◽

Resistant Bacteria ◽

Oral Microbiota ◽

Innate Defense

Growing evidence suggests the existence of new antibiotic resistance mechanisms. Recent studies have revealed that quorum-quenching enzymes, such as MacQ, are involved in both antibiotic resistance and cell-cell communication. Furthermore, some small bacterial regulatory RNAs, classified into RNA attenuators and small RNAs, modulate the expression of resistance genes. For example, small RNA sprX, can shape bacterial resistance to glycopeptide antibiotics via specific downregulation of protein SpoVG. Moreover, some bacterial lipocalins capture antibiotics in the extracellular space, contributing to severe multidrug resistance. But this defense mechanism may be influenced by Agr-regulated toxins and liposoluble vitamins. Outer membrane porin proteins and efflux pumps can influence intracellular concentrations of antibiotics. Alterations in target enzymes or antibiotics prevent binding to targets, which act to confer high levels of resistance in respiratory/oral bacteria. As described recently, horizontal gene transfer, including conjugation, transduction and transformation, is common in respiratory/oral microflora. Many conjugative transposons and plasmids discovered to date encode antibiotic resistance proteins and can be transferred from donor bacteria to transient recipient bacteria. New classes of mobile genetic elements are also being identified. For example, nucleic acids that circulate in the bloodstream (circulating nucleic acids) can integrate into the host cell genome by up-regulation of DNA damage and repair pathways. With multidrug resistant bacteria on the rise, new drugs have been developed to combate bacterial antibiotic resistance, such as innate defense regulators, reactive oxygen species and microbial volatile compounds. This review summaries various aspects and mechanisms of antibiotic resistance in the respiratory/oral microbiota. A better understanding of these mechanisms will facilitate minimization of the emergence of antibiotic resistance.

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The Activity of Alkanna Species in vitro Culture and Intact Plant Extracts Against Antibiotic Resistant Bacteria

Current Pharmaceutical Design ◽

10.2174/1381612825666190716112510 ◽

2019 ◽

Vol 25 (16) ◽

pp. 1861-1865 ◽

Cited By ~ 1

Author(s):

Naira Sahakyan ◽

Margarit Petrosyan ◽

Armen Trchounian

Keyword(s):

Antibiotic Resistance ◽

Antibacterial Agents ◽

Bacterial Resistance ◽

Antimicrobial Agents ◽

Resistant Bacteria ◽

Plant Origin ◽

Bacterial Strains ◽

Biotechnological Production ◽

Antibiotic Resistant

Overcoming the antibiotic resistance is nowadays a challenge. There is still no clear strategy to combat this problem. Therefore, the urgent need to find new sources of antibacterial agents exists. According to some literature, substances of plant origin are able to overcome bacterial resistance against antibiotics. Alkanna species plants are among the valuable producers of these metabolites. But there is a problem of obtaining the standardized product. So, this review is focused on the discussion of the possibilities of biotechnological production of antimicrobial agents from Alkanna genus species against some microorganisms including antibiotic resistant bacterial strains.

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Some approaches to new antibacterial agents

Pure and Applied Chemistry ◽

10.1351/pac200779122143 ◽

2007 ◽

Vol 79 (12) ◽

pp. 2143-2153 ◽

Cited By ~ 12

Author(s):

John B. Bremner

Keyword(s):

Bacterial Resistance ◽

Efflux Pump ◽

Transmembrane Protein ◽

Resistance Mechanism ◽

Resistance Mechanisms ◽

Target Site ◽

Resistant Bacteria ◽

General Strategy ◽

Dual Action ◽

Hybrid Drugs

Bacteria use a number of resistance mechanisms to counter the antibacterial challenge, and one of these is the expression of transmembrane protein-based efflux pumps which can pump out antibacterials from within the cells, thus lowering the antibacterial concentration to nonlethal levels. For example, in S. aureus, the NorA pump can pump out the antibacterial alkaloid berberine and ciprofloxacin. One general strategy to reduce the health threat of resistant bacteria is to block a major bacterial resistance mechanism at the same time as interfering with another bacterial pathway or target site. New developments of this approach in the context of dual-action prodrugs and dual-action (or hybrid) drugs in which one action is targeted at blocking the NorA efflux pump and the second action at an alternative bacterial target site (or sites) for the antibacterial action are discussed. The compounds are based on a combination of 2-aryl-5-nitro-1H-indole derivatives (as the NorA efflux pump blocking component) and derivatives of berberine. General design principles, syntheses, antibacterial testing, and preliminary work on modes of action studies are discussed.

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Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action

Scientific Reports ◽

10.1038/srep41206 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Joseph W. Ndieyira ◽

Joe Bailey ◽

Samadhan B. Patil ◽

Manuel Vögtli ◽

Matthew A. Cooper ◽

...

Keyword(s):

Drug Target ◽

Pathogenic Bacteria ◽

Bacterial Resistance ◽

Mechanical Response ◽

Solvable Model ◽

New Drugs ◽

Resistant Bacteria ◽

Drug Resistant ◽

Bacterial Surface ◽

Membrane Effects

Abstract The alarming increase of pathogenic bacteria that are resistant to multiple antibiotics is now recognized as a major health issue fuelling demand for new drugs. Bacterial resistance is often caused by molecular changes at the bacterial surface, which alter the nature of specific drug-target interactions. Here, we identify a novel mechanism by which drug-target interactions in resistant bacteria can be enhanced. We examined the surface forces generated by four antibiotics; vancomycin, ristomycin, chloroeremomycin and oritavancin against drug-susceptible and drug-resistant targets on a cantilever and demonstrated significant differences in mechanical response when drug-resistant targets are challenged with different antibiotics although no significant differences were observed when using susceptible targets. Remarkably, the binding affinity for oritavancin against drug-resistant targets (70 nM) was found to be 11,000 times stronger than for vancomycin (800 μM), a powerful antibiotic used as the last resort treatment for streptococcal and staphylococcal bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Using an exactly solvable model, which takes into account the solvent and membrane effects, we demonstrate that drug-target interactions are strengthened by pronounced polyvalent interactions catalyzed by the surface itself. These findings further enhance our understanding of antibiotic mode of action and will enable development of more effective therapies.

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Assessment of the Antibacterial Efficacy of Halicin against Pathogenic Bacteria

Antibiotics ◽

10.3390/antibiotics10121480 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1480

Author(s):

Rayan Y. Booq ◽

Essam A. Tawfik ◽

Haya A. Alfassam ◽

Ahmed J. Alfahad ◽

Essam J. Alyamani

Keyword(s):

Pathogenic Bacteria ◽

Wide Spectrum ◽

New Technology ◽

Cost Effective ◽

Multidrug Resistant ◽

New Drugs ◽

Resistant Bacteria ◽

Antibacterial Drug ◽

Bacterial Strains ◽

Zones Of Inhibition

Artificial intelligence (AI) is a new technology that has been employed to screen and discover new drugs. Using AI, an anti-diabetic treatment (Halicin) was nominated and proven to have a unique antibacterial activity against several harmful bacterial strains, including multidrug-resistant bacteria. This study aims to explore the antibacterial effect of halicin and microbial susceptibility using the zone of inhibition and the minimum inhibition concentration (MIC) values while assessing the stability of stored halicin over a period of time with cost-effective and straightforward methods. Linear regression graphs were constructed, and the correlation coefficient was calculated. The new antibacterial agent was able to inhibit all tested gram-positive and gram-negative bacterial strains, but in different concentrations—including the A. baumannii multidrug-resistant (MDR) isolate. The MIC of halicin was found to be 16 μg/mL for S. aureus (ATCC BAA-977), 32 μg/mL for E. coli (ATCC 25922), 128 μg/mL for A. baumannii (ATCC BAA-747), and 256 μg/mL for MDR A. baumannii. Upon storage, the MICs were increased, suggesting instability of the drug after approximately a week of storage at 4 °C. MICs and zones of inhibition were found to be high (R = 0.90 to 0.98), suggesting that halicin has a promising antimicrobial activity and may be used as a wide-spectrum antibacterial drug. However, the drug’s pharmacokinetics have not been investigated, and further elucidation is needed.

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Colistin Resistance in Enterobacterales Strains – A Current View

Polish Journal of Microbiology ◽

10.33073/pjm-2019-055 ◽

2019 ◽

Vol 68 (4) ◽

pp. 417-427 ◽

Cited By ~ 3

Author(s):

ELŻBIETA M. STEFANIUK ◽

STEFAN TYSKI

Keyword(s):

Bacterial Resistance ◽

Treatment Options ◽

Animal Husbandry ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Current View ◽

Dilution Method ◽

Bacterial Strains ◽

Plant Cultivation ◽

Severe Infections

Colistin is a member of cationic polypeptide antibiotics known as polymyxins. It is widely used in animal husbandry, plant cultivation, animal and human medicine and is increasingly used as one of the last available treatment options for patients with severe infections with carbapenem-resistant Gram-negative bacilli. Due to the increased use of colistin in treating infections caused by multidrug-resistant (MDR) bacteria, the resistance to this antibiotic ought to be monitored. Bacterial resistance to colistin may be encoded on transposable genetic elements (e.g. plasmids with the mcr genes). Thus far, nine variants of the mcr gene, mcr-1 – mcr-9, have been identified. Chromosomal resistance to colistin is associated with the modification of lipopolysaccharide (LPS). Various methods, from classical microbiology to molecular biology methods, are used to detect the colistin-resistant bacterial strains and to identify resistance mechanisms. The broth dilution method is recommended for susceptibility testing of bacteria to colistin.

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