Ion Transport Modulators as Antimycobacterial Agents

Abstract

There is an urgent need for better and safer therapeutic interventions for tuberculosis (TB). We assessed the effects of FDA-approved ion transport modulators, namely, ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide (HCTZ), metformin, omeprazole, pantoprazole, phenytoin, verapamil, and drug X and Y on the growth of free and intracellular Mycobacterium bovis BCG. Free and intracellular M. bovis BCG were cultured in the presence or absence of the test drugs for 3 to 9 days and then quantified. For both free and intracellular bacteria, cultures that were exposed to furosemide, phenytoin, or drug Y yielded lower bacteria counts compared to drug-free controls ( $p<0.05$ ). The same was observed with diazoxide, HCTZ, verapamil, and drug X, but only for intracellular M. bovis BCG ( $p<0.05$ ). To assess the effects of the drugs on bactericidal activity of rifampicin, free and intracellular M. bovis BCG were treated with rifampicin alone or in combination with each of the thirteen test drugs for 3 to 9 days. For extracellular bacteria, higher bacteria clearance rates were observed in cultures exposed to rifampicin in combination with amiloride HCl, diazoxide, digoxin, furosemide, HCTZ, metformin, pantoprazole, phenytoin, drug X, or drug Y than those exposed to rifampicin alone, indicating that rifampicin had a synergistic effect with these test drugs. Rifampicin was also synergistic with ambroxol HCl, diazoxide, digoxin, furosemide, HCTZ, omeprazole, pantoprazole, phenytoin, verapamil, and drug X against intracellular M. bovis BCG. The antimycobacterial properties exhibited by the ion transport modulators in this study make them viable candidates as adjuncts to the current anti-TB regimens.