Abstract
BackgroundThe rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions has gained special attention in the current scenario of accelerated drug development for several global infectious diseases. In a similar effort, previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis.ObjectivesWe aimed to reveal the whole-cell phenotypic and transcriptomic effects of carprofen in mycobacteria.MethodsIntegrative molecular and microbiological approaches such as resazurin microtitre plate assay, high-throughput spot-culture growth inhibition assay, whole-cell efflux inhibition, biofilm inhibition and microarray analyses were performed. Analogues of carprofen were also synthesized and assessed for their antimycobacterial activity.ResultsCarprofen was found to be a bactericidal drug that inhibited mycobacterial drug efflux mechanisms. It also restricted mycobacterial biofilm growth. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential. The pleiotropic nature of carprofen’s anti-TB action may explain why spontaneous drug-resistant mutants could not be isolated in practice.ConclusionsThis immunomodulatory drug and its chemical analogues have the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations.
Highlights
In 2018, 10 million people developed active TB and an estimated 1.5 million died from the disease.[1]
Ibuprofen and diclofenac enhance the activity of pyrazinamide and streptomycin, respectively, when
ethidium bromide (EtBr) accumulation and efflux assays performed on M. smegmatis exposed to a subinhibitory concentration of carprofen (62.5 mg/L, 0.25% MIC), showed carprofen to inhibit efflux pumps to the same extent as the potent efflux pump inhibitor verapamil (Figure 1a and b)
Summary
In 2018, 10 million people developed active TB and an estimated 1.5 million died from the disease.[1] Since the introduction of the multidrug therapeutic regimen for drug-susceptible (DS)-TB, research priorities have focused elsewhere, resulting in only three new anti-TB drugs being released over the last 40 years. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain relief. The rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis
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