Abstract
There is an urgent need to develop new drug treatment strategies to control the global spread of drug-sensitive and multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). The ß-lactam class of antibiotics is among the safest and most widely prescribed antibiotics, but they are not effective against M. tuberculosis due to intrinsic resistance. This study shows that 2-aminoimidazole (2-AI)-based small molecules potentiate ß-lactam antibiotics against M. tuberculosis. Active 2-AI compounds significantly reduced the minimal inhibitory and bactericidal concentrations of ß-lactams by increasing M. tuberculosis cell envelope permeability and decreasing protein secretion including ß-lactamase. Metabolic labeling and transcriptional profiling experiments revealed that 2-AI compounds impair mycolic acid biosynthesis, export and linkage to the mycobacterial envelope, counteracting an important defense mechanism reducing permeability to external agents. Additionally, other important constituents of the M. tuberculosis outer membrane including sulfolipid-1 and polyacyltrehalose were also less abundant in 2-AI treated bacilli. As a consequence of 2-AI treatment, M. tuberculosis displayed increased sensitivity to SDS, increased permeability to nucleic acid staining dyes, and rapid binding of cell wall targeting antibiotics. Transcriptional profiling analysis further confirmed that 2-AI induces transcriptional regulators associated with cell envelope stress. 2-AI based small molecules potentiate the antimicrobial activity of ß-lactams by a mechanism that is distinct from specific inhibitors of ß-lactamase activity and therefore may have value as an adjunctive anti-TB treatment.
Highlights
The ongoing, global spread of tuberculosis (TB), is due in part to the lack of new and more effective antimicrobial drugs to treat drug-sensitive and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (M. tuberculosis) [1]
Based on the observation that 2B8 treated M. tuberculosis failed to grow in the presence of carbenicillin, it was hypothesized that 2-AI compounds could potentiate ß-lactams against mycobacteria
The MICs of multiple ß-lactams against M. tuberculosis H37Rv and M. smegmatis were evaluated in the presence or absence of 2-AI compounds
Summary
The ongoing, global spread of tuberculosis (TB), is due in part to the lack of new and more effective antimicrobial drugs to treat drug-sensitive and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (M. tuberculosis) [1]. Treating drug-sensitive TB is challenging and requires a minimum six month course of combination antimicrobial drug therapy consisting of the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide that result in undesirable side-effects in some patients [3]. Treatment of MDR-TB is considerably more difficult and expensive requiring stronger and potentially more toxic drug combination therapy lasting approximately 2 years [2]. The current pipeline of new anti-TB drugs for the treatment of resistant infections have unproven efficacy with undesirable side effects [4, 5]
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