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Review
. 2019 Sep 1;43(5):490-516.
doi: 10.1093/femsre/fuz014.

Antibiotic resistance breakers: current approaches and future directions

Mark Laws  1 , Ali Shaaban  1 , Khondaker Miraz Rahman  1
Affiliations
Review

Antibiotic resistance breakers: current approaches and future directions

Mark Laws et al. FEMS Microbiol Rev. .

Abstract

Infections of antibiotic-resistant pathogens pose an ever-increasing threat to mankind. The investigation of novel approaches for tackling the antimicrobial resistance crisis must be part of any global response to this problem if an untimely reversion to the pre-penicillin era of medicine is to be avoided. One such promising avenue of research involves so-called antibiotic resistance breakers (ARBs), capable of re-sensitising resistant bacteria to antibiotics. Although some ARBs have previously been employed in the clinical setting, such as the β-lactam inhibitors, we posit that the broader field of ARB research can yet yield a greater diversity of more effective therapeutic agents than have been previously achieved. This review introduces the area of ARB research, summarises the current state of ARB development with emphasis on the various major classes of ARBs currently being investigated and their modes of action, and offers a perspective on the future direction of the field.

Keywords: ESKAPEE; antibiotic resistance breakers; beta-lactamase inhibitors; combination therapy; efflux pump inhibitors; membrane permeabilisers.

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Figures

Figure 1.
Figure 1.
Bacterial resistance mechanisms to antibiotics. 1) Increased drug efflux; 2) decreased drug uptake; 3) drug modification/destruction and 4) target modification.
Figure 2.
Figure 2.
Classic BLIs. Structures of clavulanic acid (top), sulbactam (middle left), tazobactam (middle right), brobactam (bottom left) and AAI101 (bottom right) (English et al. ; Reading, Farmer and Cole ; Aronoff et al. ; Wise et al. ; Mushtaq et al. ; Nordmann et al. 2014).
Figure 3.
Figure 3.
The DABCOs. General structure of DABCOs (left) and structure of ETX2514 (right) (Mangion et al. ; Durand-Reville et al. 2017).
Figure 4.
Figure 4.
The BATSIs. Structure of vaborbactam (left) and VNRX-5133 (right) (Hecker et al. ; Docquier et al. 2018).
Figure 5.
Figure 5.
The Polymyxins. General structure of the polymyxins (Velkov et al. 2010).
Figure 6.
Figure 6.
Efflux Substrate Competition. Competition for pump binding between discrete EPI and antibiotic molecules.
See this image and copyright information in PMC

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