Bifunctional antibiotic hybrids: A review of clinical candidates

Abstract

Antibiotic resistance is a top threat to human health and a priority across the globe. This problematic issue is accompanied by the decline of new antibiotics in the pipeline over the past 30 years. In this context, an urgent need to develop new strategies to combat antimicrobial resistance is in great demand. Lately, among the possible approaches used to deal with antimicrobial resistance is the covalent ligation of two antibiotic pharmacophores that target the bacterial cells through a dissimilar mode of action into a single hybrid molecule, namely hybrid antibiotics. This strategy exhibits several advantages, including better antibacterial activity, overcoming the existing resistance towards individual antibiotics, and may ultimately delay the onset of bacterial resistance. This review sheds light on the latest development of the dual antibiotic hybrids pipeline, their potential mechanisms of action, and challenges in their use.

Keywords: antibiotic pipeline; antibiotic resistance; drug combinations; drug synthesis; hybrid antibiotics.

FIGURE 1

Types of antibacterial interactions for antibiotic combinations (Created with BioRender.com). If the Drug A/B combination is synergistic (A), the combined inhibition of growth (∼75%) would exceed the calculated cumulative antibacterial effect contributed by Drug A (∼25%) and Drug B (∼25%). If the Drug A/B combination is additive (B), the combined inhibition of growth would be equivalent to the calculated cumulative effect (∼50% growth inhibition). If Drugs A and B are indifferent (C), neither of them augments nor subtracts from each other’s efficacies when combined. If Drugs A and B are antagonistic (D), the resulting combined effect results in a considerable decrease in bacterial growth inhibition (Pokrovskaya and Baasov, 2010).

FIGURE 2

Structures of TD-1792 1, THRX-169797 2, vancomycin 3, and TD-1607 4.

FIGURE 3

Synthetic scheme of TD-1792.

FIGURE 4

DNA replication and expression in bacteria and the corresponding clinical antibiotic classes, quinolones (A), rifamycins (B), and oxazolidinones (C) targeting the respective enzymes involved (Created with BioRender.com) (Bozdogan and Appelbaum, 2004; Goldstein, 2014; Pham et al., 2019).

FIGURE 5

Structures of rifamycin hybrids TNP-2092 13 and TNP-2198 24.

FIGURE 6

Synthetic scheme of TNP-2092.

FIGURE 7

Synthetic scheme of TNP-2198.

FIGURE 8

Structures of oxazolidinone hybrids Cadazolid 31 and DNV-3681 32.

FIGURE 9

Synthetic scheme of DNV-3681 and DNV-3837 (Hubschwerlen et al., 2012).

FIGURE 10

Antibacterial mechanisms of dual hybrid candidates (Created with BioRender.com). TD-1792 simultaneously binds lipid II and PBP (A, Black), TNP-2092 inhibits both RNA polymerase and type II DNA topoisomerases (B, Blue), TNP-2198 inhibits transcription and concurrently damages DNA (C, Brown), DNV-3681 inhibits both protein synthesis and DNA replication (D, Green).