Chemical Basis of Combination Therapy to Combat Antibiotic Resistance

Abstract

The antimicrobial resistance crisis is a global health issue requiring discovery and development of novel therapeutics. However, conventional screening of natural products or synthetic chemical libraries is uncertain. Combination therapy using approved antibiotics with inhibitors targeting innate resistance mechanisms provides an alternative strategy to develop potent therapeutics. This review discusses the chemical structures of effective β-lactamase inhibitors, outer membrane permeabilizers, and efflux pump inhibitors that act as adjuvant molecules of classical antibiotics. Rational design of the chemical structures of adjuvants will provide methods to impart or restore efficacy to classical antibiotics for inherently antibiotic-resistant bacteria. As many bacteria have multiple resistance pathways, adjuvant molecules simultaneously targeting multiple pathways are promising approaches to combat multidrug-resistant bacterial infections.

Figure 1

Mechanism of β-lactam antibiotic hydrolysis by (A) serine β-lactamases (Ser-BLs) and (B) metallo-β-lactamases (MBLs).

Figure 2

General mechanism of β-lactamase inhibitors. (A) Acylation of serine-β-lactamases (Ser-BLs) by tazobactam to form an ester linkage. (B) Reversible acylation of Ser-BLs by avibactam to form a carbamoyl linkage. (C) Bisthiazolidines bind to the dizinc centers of metallo-β-lactamases (MBLs) via a free thiol group. (D) Boronic acid inhibitors form tetrahedral intermediates with β-lactamases.

Scheme 1. Chemical Structure of β-Lactamase Inhibitors: (a)–(e) β-Lactam-Ring-Containing Inhibitors; (f)–(h) Diazabicyclooctane-Containing inhibitors; (i)–(o) Metallo-β-Lactamase Inhibitors; (p) and (q) Other Polymeric Inhibitors

Figure 3

(A) Chemical structure of the E. coli lipopolysaccharide (LPS). The O-antigen, core oligosaccharide, and lipid A, which forms ionic cross-links with divalent ions, are displayed. Lipid A structures of P. aeruginosa (B) and K. pneumoniae (C) are shown.

Scheme 2. Chemical Structures of Outer Membrane Permeabilizers

Figure 4

(A) Schematic representation of the five main types of bacterial efflux systems and their energy sources. (B) Representative tripartite complex of two RND efflux pumps: AcrA-AcrB-TolC and MexA-MexB-OprM. (C) Schematic illustration of the three-step rotating substrate efflux mechanism: access, binding, and extrusion.

Scheme 3. Chemical Structures of Efflux Pump Inhibitors