2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain

Abstract

There is an urgent need to develop new drugs against tuberculosis. In particular, it is critical to target drug tolerant Mycobacterium tuberculosis (M. tuberculosis), responsible, in part, for the lengthy antibiotic regimen required for treatment. We previously postulated that the presence of in vivo biofilm-like communities of M. tuberculosis could contribute to this drug tolerance. Consistent with this hypothesis, certain 2-aminoimidazole (2-AIs) molecules with anti-biofilm activity were shown to revert mycobacterial drug tolerance in an in vitro M. tuberculosis biofilm model. While exploring their mechanism of action, it was serendipitously observed that these 2-AI molecules also potentiated β-lactam antibiotics by affecting mycobacterial protein secretion and lipid export. As these two bacterial processes are energy-dependent, herein it was evaluated if 2-AI compounds affect mycobacterial bioenergetics. At low concentrations, 2B8, the lead 2-AI compound, collapsed both components of the proton motive force, similar to other cationic amphiphiles. Interestingly, however, the minimum inhibitory concentration of 2B8 against M. tuberculosis correlated with a higher drug concentration determined to interfere with the mycobacterial electron transport chain. Collectively, this study elucidates the mechanism of action of 2-AIs against M. tuberculosis, providing a tool to better understand mycobacterial bioenergetics and develop compounds with improved anti-mycobacterial activity.

Fluorescein Derivatives as Antibacterial Agents Acting via Membrane Depolarization

“…The main arguments in favor of Mitchell's chemiosmotic theory were based on the ability of uncouplers to cause the collapse of the membrane potential by carrying protons across membranes. At present, there is a revival of interest in uncouplers because of the growing evidence of their broad-spectrum therapeutic efficacy [1][2][3][4][5][6][7][8][9], including antibacterial potency [10][11][12][13][14][15][16][17][18][19], which was actually found very early [20]. To this end, a series of esters of fluorescein were obtained and studied at our laboratory, manifesting themselves as rather effective mitochondrial uncouplers [21][22][23].…”

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

“…Kumar et al screened a set of 700 compounds from the CSIR-IIIM repository for inhibition of mycobacterial ATP synthase activity using IMVs of M. smeg, leading to the identification of two compounds, the thiazolidine 5228485 and the cyclohexanediones 5220632. Both compounds inhibited ATP synthesis in IMVs and had MICs in the low micromolar range [184]. These bactericidal compounds were active against drug-resistant M. tb strains and non-replicating M. tb without apparent cytotoxicity [184].…”

“…Both compounds inhibited ATP synthesis in IMVs and had MICs in the low micromolar range [184]. These bactericidal compounds were active against drug-resistant M. tb strains and non-replicating M. tb without apparent cytotoxicity [184]. Mutants selected against each compound were cross-resistant to BDQ, although resistance studies additionally suggest that these compounds may inhibit a secondary target besides the ATP synthase [184].…”

“…These bactericidal compounds were active against drug-resistant M. tb strains and non-replicating M. tb without apparent cytotoxicity [184]. Mutants selected against each compound were cross-resistant to BDQ, although resistance studies additionally suggest that these compounds may inhibit a secondary target besides the ATP synthase [184]. Further SAR and mechanistic studies are needed to fully understand the mechanism of action and for the development of these two new classes of ATP synthase inhibitors.…”

Second‐Generation Meridianin Analogues Inhibit the Formation of Mycobacterium smegmatis Biofilms and Sensitize Polymyxin‐Resistant Gram‐Negative Bacteria to Colistin

“…[7] We have previously demonstrated that activity against M. smegmatis often translates to activity against M. tuberculosis. [8,9] Recently, we reported that analogues of the marine natural product meridianin D, 1 (Figure 1), inhibit and disperse biofilms of M. smegmatis. [10] Lead compound 2 was shown to be superior to 1 and demonstrated the ability to inhibit biofilms at low micromolar concentrations as well as the ability to disperse preformed biofilms.…”