Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs

Abstract

ABSTRACT Introduction: In 2018, an estimated 377,000 people developed multidrug-resistant tuberculosis (MDR-TB), urging for new effective treatments. In the last years, it has been accepted that efflux pumps play an important role in the evolution of drug resistance. Strategies are required to mitigate the consequences of the activity of efflux pumps. Areas covered: Based upon the literature available in PubMed, up to February 2020, on the diversity of efflux pumps in Mycobacterium tuberculosis and their association with drug resistance, studies that identified efflux inhibitors and their effect on restoring the activity of antimicrobials subjected to efflux are reviewed. These support a new strategy for the development of anti-TB drugs, including efflux inhibitors, using in silico drug repurposing. Expert opinion: The current literature highlights the contribution of efflux pumps in drug resistance in M. tuberculosis and that efflux inhibitors may help to ensure the effectiveness of anti-TB drugs. However, despite the usefulness of efflux inhibitors in in vitro studies, in most cases their application in vivo is restricted due to toxicity. In a time when new drugs are needed to fight MDR-TB and extensively drug-resistant TB, cost-effective strategies to identify safer efflux inhibitors should be implemented in drug discovery programs.