Repurposing Screen Identifies Unconventional Drugs With Activity Against Multidrug Resistant Acinetobacter baumannii

Abstract

Antibiotic-resistant nosocomial infections are an emerging public health issue; carbapenem-resistant gram-negative bacteria such as Acinetobacter baumannii are among the pathogens against which new therapeutic agents are desperately needed. Drug repurposing has recently emerged as an alternative approach to rapidly identifying effective drugs and drug combinations to combat drug resistant bacteria. We performed a drug repurposing screen against a highly virulent, multidrug resistant, Acinetobacter baumannii strain AB5075. This strain, isolated from a patient, is resistant to 25 first-line antibiotics for gram-negative bacteria. A compound screen using a bacterial growth assay led to identification and confirmation of 43 active compounds. Among these confirmed compounds, seven are approved drugs or pharmacologically active compounds for non-antimicrobial indications. Three of these drugs, 5-fluorouracil, fluspirilene, and Bay 11-7082 resensitized strain AB5075 to azithromycin and colistin in a two-drug combination format. The approach using a drug repurposing screen with a pathogen sample isolated from a patient and a high throughput bacterial growth assay led to the successful identification of new drug combinations to overcome a multidrug resistant bacterial infection.

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].…”

Strategies to Combat Persistent Infectious Diseases

“…One year ago, Cheng et al [73] used an A. baumannii strain resistant to most antibiotics (AB5075) and reported that 3 antineoplastics (5-fluorouracil, 6-thioguanine and pifithrin-μ), an anti-rheumatic (auranofin), an antipsychotic (fluspirilene), an anti-inflammatory (Bay 11-7082) and an alcohol detergent (disulfiram) inhibited the growth of a MDR A. baumannii. 5-fluorouracil and 6-thioguanine seemed to be the best candidates among all the repurposed drugs in the treatment of MDR clinical A. baumannii: their IC90 values and MIC were lower than standard plasma drug concentration levels in human, suggesting a possible use without major adverse events.…”

Bacterial Cytological Profiling as a Tool To Study Mechanisms of Action of Antibiotics That Are Active against Acinetobacter baumannii

“…These screens resulted in the discovery of many antibiotics exhibiting both broad spectrum, such as streptomycin (19), and mycobacterium-specific activity, including isoniazid, pyrazinamide, ethionamide, ethambutol (4), and bedaquiline (20). Recently, Gramspecific (21)(22)(23)(24) and pathogen-specific (25,26) antibiotic discovery were also proven to be successful, leading to the identification of narrow spectrum compounds, including some that are active only against A. baumannii (27)(28)(29). As more candidate compounds are revealed through screening, there will be a need for better methods to elucidate their mechanism of action (MOA) in A. baumannii.…”