Enhancement of the antituberculosis activity of weak acids by inhibitors of energy metabolism but not by anaerobiosis suggests that weak acids act differently from the front-line tuberculosis drug pyrazinamide

Abstract

Mycobacterium tuberculosis is uniquely susceptible to weak acids compared with other mycobacteria or bacteria. The antituberculosis activity of the front-line drug pyrazinamide (PZA), a weak acid (pyrazinoic acid) precursor, can be enhanced by inhibitors of energy metabolism and anaerobiosis. Here, we investigated the effect of inhibitors of energy metabolism and anaerobiosis on weak acid activity against M. tuberculosis in general. The susceptibility of M. tuberculosis to benzoic acid (BA) esters and amides was determined alone and in the presence of inhibitors of energy metabolism such as N,N'-dicyclohexylcarbodiimide (DCCD) and azide and also under anaerobic conditions in the form of MIC and drug exposure followed by colony count. Some BA esters such as propyl hydroxybenzoic acid and 4-dodecyloxylbenzoic acid had significant activity whereas amides of BA had no activity. As for PZA, inhibitors of energy metabolism DCCD and azide enhanced the antituberculosis activity of weak acids under normal atmospheric oxygen tension. However, unlike PZA, weak acids did not show antituberculosis activity and the inhibitors of energy metabolism did not enhance the weak acid activity under anaerobic conditions. The enhancement of weak acid activity by inhibitors of energy metabolism for M. tuberculosis was not seen in other bacterial species such as Helicobacter pylori. These results suggest that while the antituberculosis activity of weak acids can be enhanced by inhibitors of energy metabolism as for PZA, weak acids act differently from PZA in that they were inactive against M. tuberculosis under anaerobic conditions. The significance of these findings is discussed in the context of the unique physiology of M. tuberculosis and the development of new tuberculosis drugs.