Conventional Antibiotics – Revitalized by New Agents

Abstract

SUMMARYBeta-lactamase inhibitors are clinically proven to revitalise old beta-lactam antibiotics by neutralising bacterial beta-lactamases. We call these compounds antibiotic resistance breakers. Unfortunately, bacteria express more than 1000 beta-lactamases, of which the metallo-betalactamases are proving difficult to neutralise. Here we describe other antibiotic resistant breakers, which are not yet in the clinic, but which potentially revitalise other classes of antibiotics. These include aminoglycoside modifying enzyme inhibitors, efflux pump inhibitors and compounds which are associated with increased permeability of the bacterial cell membrane. If it were possible to develop new antibiotic resistant breakers for many different classes of antibiotics, this approach could be a viable alternative to the more expensive single novel compound route which has been pursued for pyogenic bacterial infections.

Synergistic antibacterial effect of co-administering adipose-derived mesenchymal stromal cells and Ophiophagus hannah l-amino acid oxidase in a mouse model of methicillin-resistant Staphylococcus aureus-infected wounds

“…AMPs are known to increase the permeability of bacterial membranes to synergize with conventional antibiotics [29]. Chimeric AMPs synthesized by combinations of functional groups from natural AMPs have demonstrated synergistic effects with conventional antibiotics including cefotaxime, ciprofloxacin, and erythromycin [30].…”

The small quinolone derived compound HT61 enhances the effect of tobramycin against Pseudomonas aeruginosa in vitro and in vivo

“…As an alternative to simply increasing antibiotic plasma levels, the use of multiple antibiotics in combination has been proposed as a strategy capable of slowing the emergence of antimicrobial resistance whilst also shortening the required duration of therapy (33). Antibiotics from a number of different classes have previously been reported to show synergistic effects against tobramycin resistant strains of P. aeruginosa (34), therefore enhancer strategies (or antibiotic resistance breakers), featuring low or no direct antibiotic impact, may therefore be less susceptible as a target for resistance emergence and could be a viable alternative approach (35,36) Resistance, emerging or intrinsic, is a feature of the pathogen P. aeruginosa (37). Despite the layered nature of the resistance characteristic of P. aeruginosa, compounds able to compromise the integrity of bacterial cell membranes are likely to enhance antibiotic penetration.…”

An Atlas of Anionic Antimicrobial Peptides from Amphibians

“…This latter peptide also showed the ability to potentiate the action of conventional antibiotics against MDR pathogens, and the potential advantages of this form of combination therapy are increasingly being recognised and are viewed as a major, potential strategy for combating microbial pathogens with MDR [137][138]. For example, combination treatment can potentially reduce the required dosage of individual drugs, thereby diminishing side effects, as well as, not only eliminating resistant strains, but also delaying the emergence of drug resistance [139][140]. Indeed, it has been observed that combination therapy to potentiate failing antibiotics could be an interim solution to the global problem of MDR pathogens until sufficient numbers of novel antimicrobial molecules and strategies become available [141].…”