Molecules that Inhibit Bacterial Resistance Enzymes

Abstract

Antibiotic resistance mediated by bacterial enzymes constitutes an unmet clinical challenge for public health, particularly for those currently used antibiotics that are recognized as "last-resort" defense against multidrug-resistant (MDR) bacteria. Inhibitors of resistance enzymes offer an alternative strategy to counter this threat. The combination of inhibitors and antibiotics could effectively prolong the lifespan of clinically relevant antibiotics and minimize the impact and emergence of resistance. In this review, we first provide a brief overview of antibiotic resistance mechanism by bacterial secreted enzymes. Furthermore, we summarize the potential inhibitors that sabotage these resistance pathways and restore the bactericidal activity of inactive antibiotics. Finally, the faced challenges and an outlook for the development of more effective and safer resistance enzyme inhibitors are discussed.

Keywords: antibiotic resistance; bacterial enzymes; molecules; therapeutic potential.

Figure 1

Scheme of antibiotic resistance mechanisms mediated by bacterial resistance enzymes. (A) Resistance enzymes hydrolyze the antibiotics and confer resistance. (B) Resistance enzymes modify the structure of antibiotics or antibiotic targets, preventing the antibiotics from binding to their targets and conferring resistance.

Figure 2

β-Lactams are hydrolized by (i) Ser-β-lactamase and (ii) metallo-β-lactamase [21]. The hydrolysis site on the antibiotic is marked by red arrows.

Figure 3

Ring-opening reactions catalyzed by (A) macrolide esterases [73] and (B) fosfomycin-resistance enzymes FosX/A/B [77]. The hydrolysis sites on the antibiotics are marked by red arrows.

Figure 4

Modification of kanamycin B by aminoglycoside nucleotidyltransferases (ANTs), phosphotransferases (APHs), and acetyltransferases (AACs) [87,88,89,90,91].

Figure 5

Inactivation of lincomycin/clindamycin and chloramphenicol by nucleotidyltransferases or acetyltransferases. LinA/A’/B: Lincomycin nucleotidyltransferases A/A’/B.

Figure 6

Enzyme-catalyzed inactivation of macrolides by phosphotransferases and glycosyltransferases.

Figure 7

Inactivation of (A) tetracycline and (B) streptogramin by redox enzymes [95,96,97].

Figure 8

Scheme of bacterial lipid A modified by phosphatidylethanolamine (PE) through MCR-1 [121]. The modified groups on the antibiotic are in red; pEtN: phosphoethanolamine.

Figure 9

Inhibitors of Ser-β-lactamases and metallo-β-lactamases. The chemical structures, templates, derivatives of β-lactamases inhibitors, and commonly paired antibiotics are shown.

Figure 10

Inhibitors of the fosfomycin-resistance enzyme FosA.

Figure 11

Inhibitors of aminoglycoside ANTs.

Figure 12

Inhibitors of APHs.

Figure 13

Inhibitors of AACs.

Figure 14

Inhibition of MCR-1 by molecules directly interacting with resistance enzymes or by targeting its mRNA.