A Review of Antibacterial Candidates with New Modes of Action

Abstract

There is a lack of new antibiotics to combat drug-resistant bacterial infections that increasingly threaten global health. The current pipeline of clinical-stage antimicrobials is primarily populated by "new and improved" versions of existing antibiotic classes, supplemented by several novel chemical scaffolds that act on traditional targets. The lack of fresh chemotypes acting on previously unexploited targets (the "holy grail" for new antimicrobials due to their scarcity) is particularly unfortunate as these offer the greatest opportunity for innovative breakthroughs to overcome existing resistance. In recognition of their potential, this review focuses on this subset of high value antibiotics, providing chemical structures where available. This review focuses on candidates that have progressed to clinical trials, as well as selected examples of promising pioneering approaches in advanced stages of development, in order to stimulate additional research aimed at combating drug-resistant infections.

Keywords: antibacterial; antibiotic; drug development; mechanism; mode of action; pipeline; resistance.

Figure 1

(A) Comparison of cell wall structure of Gram-positive (G+ve) bacteria, Gram-negative bacteria (G–ve), and mycobacteria (Mb). (B) Targets of clinically used antibiotics (names in green with (+) = G+ve only, in blue with (−) = G–ve only, in black = G+ve and G–ve, in magenta with (M) = Mycobacterium only.

Figure 2

Structures of cell envelope targeting antibacterials and related compounds being evaluated in clinical trials with new MoAs not found in existing drugs.

Figure 3

Cell wall, membrane protein, and extracellular pathways targeted by antibiotics with new MoAs not found in existing drugs. Abbreviations: CoA, coenzyme A; ACC, acetyl-CoA carboxylase; ACP, acyl-carrier protein; DXS, 1-deoxy-d-xylulose 5-phosphate synthase; DXR, 1-deoxyxylulose-5-phosphate reductoisomerase; IPP, isopentenyl diphosphate; C55, undecaprenyl phosphate; G3P, glyceraldehyde-3-phosphate; GT, glycosyltransferase; TP, transpeptidase; T3SS, type 3 secretion system; LPS, lipopolysaccharide.

Figure 4

Structures of preclinical cell wall targeting antibacterials and related compounds with new MoAs not found in existing antibacterial drugs (Part 1).

Figure 5

Structures of preclinical cell envelope targeting antibacterials with new MoAs not found in existing antibacterial drugs (Part 2).

Figure 6

Structures of DNA synthesis targeting antibacterials currently being evaluated in clinical trials and related compounds with new MoAs not used by antibacterial existing drugs.

Figure 7

Intracellular pathways targeted by antibiotics with new MoAs not found in existing drugs. Abbreviations: aaRS, aminoacyl-tRNA synthetase; FMN, flavin mononucleotide; EF, elongation factor; PDF, peptide deformylase; RBS, ribosome binding site.

Figure 8

Structures of preclinical DNA synthesis targeting antibacterials with new MoAs not used by existing antibacterial drugs.

Figure 9

Structures of protein synthesis targeting antibacterials currently being evaluated in clinical trials and related compounds with new MoAs not represented in existing antibacterial drugs.

Figure 10

Structures of other preclinical antibacterials with new MoAs not used by antibacterial drugs.

Figure 11

Structures of other antibacterials in clinical trials with new MoAs and related compounds not used by existing antibacterial drugs.

Figure 12

Structures of other preclinical antibacterials with new MoAs not represented in existing antibacterial drugs.

Figure 13

Structures of nontraditional antibacterials in clinical trials and related compounds with new MoAs not used by existing antibacterial drugs.

Figure 14

Structures of preclinical nontraditional antibacterials with new MoAs not represented in existing antibacterial drugs.