Strategies to Overcome Antimicrobial Resistance (AMR) Making Use of Non-Essential Target Inhibitors: A Review

Abstract

Antibiotics have always been considered as one of the most relevant discoveries of the twentieth century. Unfortunately, the dawn of the antibiotic era has sadly corresponded to the rise of the phenomenon of antimicrobial resistance (AMR), which is a natural process whereby microbes evolve in such a way to withstand the action of drugs. In this context, the identification of new potential antimicrobial targets and/or the identification of new chemical entities as antimicrobial drugs are in great demand. To date, among the many possible approaches used to deal with antibiotic resistance is the use of antibiotic adjuvants that hit bacterial non-essential targets. In this review, the author focuses on the discovery of antibiotic adjuvants and on new tools to study and reduce the prevalence of resistant bacterial infections.

Keywords: Antibiotic resistance; antibiotic adjuvant therapies; beta-lactamases inhibitors; combination therapy; efflux pump inhibitors; membrane permeabilizers; non-essential targets; virulence factors.

Figure 1

Antibiotic resistance pipeline. On the top, antibiotic introduced and, on the bottom, antibiotic resistance identified.

Figure 2

Cartoon representation of different mechanisms of antibiotic resistance. Antibiotics as red and white pills, target proteins in green.

Figure 3

(A) Chemical structures of the efflux pump inhibitors (EPIs) discussed in this review and (B) efflux pumps expressed in Gram-positives and Gram-negatives bacteria and their respectively inhibitors.

Figure 4

Chemical structures of β-lactamases inhibitors discussed in this review.

Figure 5

Chemical structures of membrane permeabilizers discussed in this review.

Figure 6

Schematic representation of the Cysteine-synthase-complex (CSC) within bacterial cell; RSAP begins with the transportation of sulfate inside the cell, followed by its reduction to bisulfide. This process is highly energy-consuming and is tuned to cellular needs. Bacteria find sulfur in the form of sulfate in the environment and actively transport it through plasma membrane. After the reduction of sulfate to bisulfide, the latter is incorporated into cysteine by a member of a large enzyme family, known as cysteine synthase complex (CSC). The CSC is composed by the enzyme serine acetyl transferase (SAT) and O-acetylserine sulfydrylase (OASS), which catalyzes the last step of cysteine biosynthesis.

Figure 7

O-Acetylserine sulfhydrilase (OASS) inhibitors discussed in this review. (A) schematic representation of the rational design of the first sulfhydrylase inhibitors based on the structural features of the OASS–SAT interaction; (B) chemical scaffold of potent inhibitors of CysM, enzyme in cysteine biosynthesis during mycobacterium dormancy; (C) chemical scaffold of fluoroalanine derivatives endowed with the ability to irreversibly inhibit both OASS-A and B isozymes.

Figure 8

Chemical structures of Quorum sensing (QS) inhibitors discussed in this review.