Uncovering interactions between mycobacterial respiratory complexes to target drug-resistant Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis remains a leading cause of infectious disease morbidity and mortality for which new drug combination therapies are needed. Mycobacterial bioenergetics has emerged as a promising space for the development of novel therapeutics. Further to this, unique combinations of respiratory inhibitors have been shown to have synergistic or synthetic lethal interactions, suggesting that combinations of bioenergetic inhibitors could drastically shorten treatment times. Realizing the full potential of this unique target space requires an understanding of which combinations of respiratory complexes, when inhibited, have the strongest interactions and potential in a clinical setting. In this review, we discuss (i) chemical-interaction, (ii) genetic-interaction and (iii) chemical-genetic interaction studies to explore the consequences of inhibiting multiple mycobacterial respiratory components. We provide potential mechanisms to describe the basis for the strongest interactions. Finally, whilst we place an emphasis on interactions that occur with existing bioenergetic inhibitors, by highlighting interactions that occur with alternative respiratory components we envision that this information will provide a rational to further explore alternative proteins as potential drug targets and as part of unique drug combinations.

F1·Fo ATP Synthase/ATPase: Contemporary View on Unidirectional Catalysis

“…It kills more people than any other infectious disease of bacterial origin. The emergence and spread of multidrug-resistant, extensively drug-resistant, and totally drug-resistant strains of M. tuberculosis is a great challenge in anti-tuberculosis treatment [ 112 , 113 ]. Thus, there is an urgent need to create potent antimycobacterial agents with a novel mechanism of action.…”

“…At the end of this section, it should be noted that the use of a specific and potent inhibitor of the mycobacterial F 1 ∙F o , in combination with inhibitors of other bioenergetics enzymes of M. tuberculosis , such as cytochrome bd and/or a bcc - aa 3 supercomplex, may have a synergistic effect [ 113 , 138 , 139 , 140 , 141 , 142 ]. This would represent an innovative pharmaceutical strategy for the treatment of highly drug-resistant tuberculosis.…”

Chemistry and Biology of Coenzyme F420 in Tuberculosis treatment

“…The unique combinations of respiratory inhibitors have been shown to have synergistic or synthetic lethal interactions, suggesting that combinations of bioenergetic inhibitors could drastically shorten treatment times. 23…”

Mycobacterium tuberculosis cell-wall and antimicrobial peptides: a mission impossible?

“…The expression of proteins responsible for AMP resistance in Gram positive-bacilli have also been documented in Mtb, such as ABC transporters ( 157 , 158 ) or mycobacterial respiratory complexes (a promising new drug target for combatting drug-resistant strains of Mtb) ( 159 , 160 ). However, to our knowledge, the long list of evasion mechanisms described for other Gram-positive bacilli has not been studied in Mtb, with the exception for lysinylation of phosphatidylglycerol (L-PG).…”