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.2015 Jan;85(1):56-78.
doi: 10.1111/cbdd.12478.

Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens

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Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens

Erin E Gill et al. Chem Biol Drug Des.2015 Jan.

Abstract

The growing number of bacterial pathogens that are resistant to numerous antibiotics is a cause for concern around the globe. There have been no new broad-spectrum antibiotics developed in the last 40 years, and the drugs we have currently are quickly becoming ineffective. In this article, we explore a range of therapeutic strategies that could be employed in conjunction with antibiotics and may help to prolong the life span of these life-saving drugs. Discussed topics include antiresistance drugs, which are administered to potentiate the effects of current antimicrobials in bacteria where they are no longer (or never were) effective; antivirulence drugs, which are directed against bacterial virulence factors; host-directed therapies, which modulate the host's immune system to facilitate infection clearance; and alternative treatments, which include such therapies as oral rehydration for diarrhea, phage therapy, and probiotics. All of these avenues show promise for the treatment of bacterial infections and should be further investigated to explore their full potential in the face of a postantibiotic era.

Keywords: antimicrobial peptide; antivirulence; efflux pump; immunomodulatory peptide; outer membrane permeabilizer; phage therapy; probiotic; quorum sensing; type III secretion system; β-lactamase.

© 2014 The Authors. Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

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Figures

Figure 1
Figure 1
Selected Antiresistance and Antivirulence Agents and their Mechanisms of Action. Cationic peptides (54) and EDTA (55) are outer membrane permeabilizing agents that make the outer membrane more amenable to the penetration of antibiotics. Capsaicin (175) is an efflux pump inhibitor that acts on the NorA pump ofS. aureusto impede the efflux of the antibiotic ciprofloxacin from inside the cell. Clavulanic acid (165) is a lactamase inhibitor that inhibits the action of lactamase on penicillin, therefore increasing penicillin's effectiveness. Savirin (86) is a quorum-sensing inhibitor that arrests the binding of AgrA to the P2 promoter, which is upstream of aS. aureusquorum-sensing operon. Binding of AgrA to the P2 promoter induces transcription of the quorum-sensing operon, so savirin's action prevents quorum-sensing gene expression. Urtoxazumab (97) is a toxin inhibitor that inactivatesE. coliShiga-like toxin 2. Shiga-like toxin 2 is produced by late cycle phage genes and then released from the cell upon lysis. The toxin is then bound and inactivated by the urtoxazumab antibody. CoilA and CoilB (113,114) are peptides that inhibit the assembly of the type III secretion system apparatus. By preventing the formation of the type III secretion system, secretion of effector proteins (such as Tir) is effectively stopped.
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