New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold

TB is still a global health problem. The selection and spread of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains represents a threat for global TB control. The reappearance of TB has driven an increased interest in understanding the mechanisms of drug action and drug resistance, which could provide a significant contribution in the development of new antimicrobials. In this article, the authors describe the mode of action and the resistance mechanisms of the principal first- and second-line antitubercular agents, namely isoniazid, ethionamide, ethambutol, D-cycloserine, rifamycins, fluoroquinolones, streptomycin, linezolid and pyrazinamide. A brief outline of the seven drugs in clinical development is reported, showing how the development of new TB drugs is still required.

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“…BM212 (Figure 6) was the most suited compound of this new class of derivatives and it is still under investigation [116][117][118].…”

Section: New Promising Drugs For Tb: Molecules In Clinical Developmentmentioning

confidence: 99%

Mycobacterium Tuberculosis : Drug Resistance and Future Perspectives

2009

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“…While the apparent promiscuity of MmpL3 as a drug target may owe to unusual vulnerability or druggability, the diversity of the chemical scaffolds identified and important differences in their spectra of activity led us to question their direct mechanism of action on the transporter. In particular, the fact that SQ109, BM212, and THPP compounds display inhibitory activity against a broad spectrum of bacterial and fungal pathogens that are devoid of mycolic acids (7,20,21), while AUs and indolecarboxamides specifically target mycobacteria (17,19), suggests that the three first compounds had at least one broader-spectrum target in M. tuberculosis or killed the bacterium through a different mechanism, impacting MmpL3 only indirectly. Another important difference between the MmpL3 inhibitors resides in their activities against nonreplicating M. tuberculosis bacilli.…”

mentioning

confidence: 99%

Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis

Upadhyay‬

Fontes

et al. 2014

Antimicrob Agents Chemother

170

198

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dMmpL3, a resistance-nodulation-division (RND) superfamily transporter, has been implicated in the formation of the outer membrane of Mycobacterium tuberculosis; specifically, MmpL3 is required for the export of mycolic acids in the form of trehalose monomycolates (TMM) to the periplasmic space or outer membrane of M. tuberculosis. Recently, seven series of inhibitors identified by whole-cell screening against M. tuberculosis, including the antituberculosis drug candidate SQ109, were shown to abolish MmpL3-mediated TMM export. However, this mode of action was brought into question by the broad-spectrum activities of some of these inhibitors against a variety of bacterial and fungal pathogens that do not synthesize mycolic acids. This observation, coupled with the ability of three of these classes of inhibitors to kill nonreplicating M. tuberculosis bacilli, led us to investigate alternative mechanisms of action. Our results indicate that the inhibitory effects of adamantyl ureas, indolecarboxamides, tetrahydropyrazolopyrimidines, and the 1,5-diarylpyrrole BM212 on the transport activity of MmpL3 in actively replicating M. tuberculosis bacilli are, like that of SQ109, most likely due to their ability to dissipate the transmembrane electrochemical proton gradient. In addition to providing novel insights into the modes of action of compounds reported to inhibit MmpL3, our results provide the first explanation for the large number of pharmacophores that apparently target this essential inner membrane transporter.

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“…9). It is now accepted that SQ109 has polypharmacology properties, as it has activity on fungi and bacteria that do not possess mycolic acids [47, 48] and activity against latent cells that do not require active cell wall synthesis [49, 50]. Further investigation of SQ109's mechanism of action divulged additional inhibition of menaquinone synthesis, cellular respiration, and ATP synthesis in part due to dissipation of the proton motif force across the cytoplasmic membrane [50].…”

Section: Drugs Under Developmentmentioning

confidence: 99%

New agents for the treatment of drug-resistant Mycobacterium tuberculosis

Hoagland

Liu

Lee

et al. 2016

Advanced Drug Delivery Reviews

286

201

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Inadequate dosing and incomplete treatment regimens, coupled with the ability of the tuberculosis bacilli to cause latent infections that are tolerant of currently used drugs, have fueled the rise of multidrug-resistant tuberculosis (MDR-TB). Treatment of MDR-TB infections is a major clinical challenge that has few viable or effective solutions; therefore patients face a poor prognosis and years of treatment. This review focuses on emerging drug classes that have the potential for treating MDR-TB and highlights their particular strengths as leads including their mode of action, in vivo efficacy, and key medicinal chemistry properties. Examples include the newly approved drugs bedaquiline and delaminid, and other agents in clinical and late preclinical development pipeline for the treatment of MDR-TB. Herein, we discuss the challenges to developing drugs to treat tuberculosis and how the field has adapted to these difficulties, with an emphasis on drug discovery approaches that might produce more effective agents and treatment regimens.

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New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold

Cited by 40 publications

References 36 publications

Mycobacterium Tuberculosis : Drug Resistance and Future Perspectives

Mycobacterium Tuberculosis : Drug Resistance and Future Perspectives

Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis

New agents for the treatment of drug-resistant Mycobacterium tuberculosis

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