Drug Repurposing Approaches towards Defeating Multidrug-Resistant Gram-Negative Pathogens: Novel Polymyxin/Non-Antibiotic Combinations

Abstract

Multidrug-resistant (MDR) Gram-negative pathogens remain an unmet public health threat. In recent times, increased rates of resistance have been reported not only to commonly used antibiotics, but also to the last-resort antibiotics, such as polymyxins. More worryingly, despite the current trends in resistance, there is a lack of new antibiotics in the drug-discovery pipeline. Hence, it is imperative that new strategies are developed to preserve the clinical efficacy of the current antibiotics, particularly the last-line agents. Combining conventional antibiotics such as polymyxins with non-antibiotics (or adjuvants), has emerged as a novel and effective strategy against otherwise untreatable MDR pathogens. This review explores the available literature detailing the latest polymyxin/non-antibiotic combinations, their mechanisms of action, and potential avenues to advance their clinical application.

Keywords: antimicrobial resistance; drug repurposing; non-antibiotic agents; polymyxins.

Figure 1

Adjuvants exert anti-resistance mechanisms by inhibiting enzymes involved in antibiotic inactivation (A), blocking efflux pumps (B), disrupting membrane integrity to enable intracellular antibiotic access (C), interfering with signaling pathways leading to antibiotic resistance (D), and dispersing bacteria in biofilms to expose them to antibiotics (E) (Created with BioRender.com) [39,41].

Figure 2

Chemical structures and pharmacological mechanisms of polymyxins. (A) Structures of polymyxin B and colistin with the amino acid differences between them circled in red. (B) The bactericidal action of polymyxins against Gram-negative bacteria via targeting LPS on the outer membrane and perforating the inner membrane (Created with Biorender.com).

Figure 3

An overview of the general synergistic mechanisms of polymyxin/non-antibiotic combinations (Created with BioRender.com). (A) The combinations function via augmented membrane perforation, and (B) disruption of vital metabolic pathways, DNA replication, and gene expression contributing to resistance.