Evaluation of nitroxyl donors’ effect on mycobacteria

Abstract

Nitroxyl (HNO) is a highly elusive and reactive molecule. Nitroxyl biological effects and pharmacological potential are becoming increasingly relevant. Mycobacterium tuberculosis infection needs new and more efficient drugs. Reactive Nitrogen and Oxygen Species (RNOS) are key compounds used by the immune system to fight intracellular infections, particularly Mycobacterium tuberculosis. In this context, we analyzed HNO potential to kill mycobacteria. We evaluated the viability and biological response of mycobacteria towards HNO releasing compounds. Our results show that HNO donors can affect mycobacterial growth, for both Mycobacterium smegmatis and Mycobacterium tuberculosis. The effect can be observed using a single dose or with successive additions of lower concentrations of the donor, mimicking continuous HNO exposure. When analyzing the effect of the simultaneous addition of sub-inhibitory concentrations of HNO with antibiotics commonly used for Mycobacterium tuberculosis infection treatment we observed: a positive effect on Rifampicin, Kanamycin and Delamanid activity; and a negative effect on Isoniazid and Ethambutol activity. Regarding a possible mechanism of action, based on the recently developed fluoromycobacteriophage assay, we propose that HNO acts by interfering with general mycobacterial physiological state. The results of this study positions HNO donors as potential candidates as new drugs for a new tuberculosis treatment.