Drug Repurposing to Fight Colistin and Carbapenem-Resistant Bacteria

Abstract

The emergence of new resistance mechanisms, the failure of classical antibiotics in clinic, the decrease in the development of antibiotics in the industry are all challenges that lead us to consider new strategies for the treatment of infectious diseases. Indeed, in recent years controversy has intensified over strains resistant to carbapenem and/or colistin. Various therapeutic solutions are used to overcome administration of last line antibiotics. In this context, drug repurposing, which consists of using a non-antibiotic compound to treat multi-drug resistant bacteria (MDR), is encouraged. In this review, we first report what may have led to drug repurposing. Main definitions, advantages and drawbacks are summarized. Three major methods are described: phenotypic, computational and serendipity. In a second time we will focus on the current knowledge in drug repurposing for carbapenem and colistin-resistant bacteria with different studies describing repurposed compounds tested on Gram-negative bacteria. Furthermore, we show that drug combination therapies can increase successful by drug repurposing strategy. In conclusion, we discuss the pharmaceutical industries that have little interest in reprofiling drugs due to lack of profits. We also consider what a clinician might think of the indications of these uncommon biologists to treat MDR bacterial infections and avoid therapeutic impasses.

Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

“…Non-antibiotic compounds can be effective when used in combination with other drugs or antibiotics, although further studies must be conducted to determine effective concentrations that are clinically tolerated and safe. In terms of economic issues, we agree with Leyclit and colleagues who, in a recent review article, mentioned that pharmaceutical industries have little interest in re-profiling existing drugs due to the lack of profit [99]. However, drug repurposing can have real economic advantages, as structural and pharmacological studies were already conducted, e.g., studies concerning the bioavailability or safety profiles [83].…”

“…Thus, repurposing approved drugs may be highly effective against multiple antibiotic-resistant pathogens, taking into account the current (increasing) problem of antimicrobial ineffectiveness and resistance [83,99].…”

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

“…Developing a new chemical entity drug and delivering it to the market, known as de novo drug discovery, is a time-consuming and expensive process with increasing regulatory requirements and a high risk of failure-all of which could make the pharmaceutical industry a less desirable choice for investors. Nowadays, drug repurposing has become a successful strategy to fast-track therapeutic agents for the treatment of several emerging or rare diseases, such as AIDS, Alzheimer's disease and cancer [10,[34][35][36][37][38][39][40], but also infections with multidrug-resistant strains of clinically relevant pathogens [9,[41][42][43][44].…”

Degrasyn exhibits antibiotic activity against multi-resistant Staphylococcus aureus by modifying several essential cysteines

“…1,2 One strategy to identify novel antibacterials focuses on the repurposing of existing drugs originally developed against human proteins. 3,4 In a recent drug-repurposing screen, 5 we identified that the human deubiquitinating enzyme inhibitor degrasyn (also called WP1130) kills methicillin-sensitive S. aureus (MSSA) ( Fig. 1A and B).…”