BM 212 and its Derivatives as a New Class of Antimycobacterial Active Agents

Biava, Mariangela

doi:10.2174/0929867023368953

Cited by 26 publications

(18 citation statements)

References 16 publications

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“…BM212 was synthesized as previously reported (3,4). Briefly, 1-(4-chlorophenyl)pentane-1,4-dione was obtained by reacting the 4-Clbenzaldehyde with methyl vinyl ketone.…”

Section: Synthesis Of Bm212mentioning

confidence: 99%

“…1) proved to be active against multidrug-resistant clinical isolates, against M. tuberculosis residing within macrophages, and against Mycobacterium avium as well as other nontuberculous mycobacteria (7). The identification of BM212 as a hit within this compound class provided the stimulus to develop novel structures that could be endowed with less toxic features and better activities (3,4).…”

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confidence: 99%

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MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212

Rosa

Poce²,

Canseco

et al. 2012

Antimicrob Agents Chemother

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194

204

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The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates and Mycobacterium tuberculosis residing within macrophages as well as against Mycobacterium avium and other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. Spontaneous Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuberculosis H37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in the mmpL3 gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (mycobacterial membrane protein, large) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanide m-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [ 14 C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212.T he rise of multidrug-resistant (MDR) and extensively drugresistant (XDR) Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), makes the validation of new antitubercular agents a major global priority. Since tubercular drug resistance is chromosomally encoded (17), chemotherapeutic agents directed against new cellular targets are likely to be effective against both drug-sensitive and drug-resistant M. tuberculosis strains (5,12,13,18). Target identification and validation are usually achieved by either genetic or chemical approaches. The former has the advantage of identifying a likely cellular target a priori but yields no information with regard to the druggability of the target and the access of the drug to the target (a particular problem in mycobacteria [23]). It is therefore not surprising that no current antitubercular agents have been identified through rational drug design (23). Alternatively, the identification of a cellular target candidate through chemical screening has the advantage of knowing that the compound can bind and affect the cellular target in vivo. The identification of the target for an active compound allows the rational modification of lead candidates through medicinal chemistry while ensuring that the compound retains activity against its primary target. However, finding which proteins are inhibited by a compound can be quite challenging.We randomly screened a library of compounds to identify structures of interest for further development. Several azole compounds containing imidazole, pyrrole, toluidine, or methanamine groups were tested for antimycobacterial activity. Among them, 1-{[1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl]methyl}-4-methylpiperazine (BM212) (Fig. 1) proved to be active against multidrug-resistant clinical isolates, against M. tuberculosis residing within macrophages, and against Mycobacterium avium as well as other nontuberculous mycobacteria (7). The identification of BM21...

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“…BM212 was synthesized as previously reported (3,4). Briefly, 1-(4-chlorophenyl)pentane-1,4-dione was obtained by reacting the 4-Clbenzaldehyde with methyl vinyl ketone.…”

Section: Synthesis Of Bm212mentioning

confidence: 99%

mentioning

confidence: 99%

MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212

Rosa

Poce²,

Canseco

et al. 2012

Antimicrob Agents Chemother

Self Cite

194

204

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“…The complex lipoglycan calyx on the mycobacterial cell surface provides a significant physical barrier to intracellular-acting drugs; lack of penetration is thought to be a reason why many antibiotics show no activity against M. tuberculosis (41). Inhibition of synthesis is known to be lethal to the bacterium as evidenced by the action of isoniazid and ethambutol, and the (1), kanamycin (2a), amikamycin (2b), capreomycin (3), rifamycin (4), rifampicin (5), nalidixic acid (6), ciprofloxacin (7), ofloxacin (8), p-aminosalicyclic acid (9), isoniazid (10), ethionamide (11), ethambutol (12), and cycloserine (13).…”

Section: Antimycobacterial Leads With Known Mode Of Actionmentioning

confidence: 99%

New Small-Molecule Synthetic Antimycobacterials

Ballell

Field

Duncan

et al. 2005

Antimicrob Agents Chemother

166

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“…This class has been under investigation by an academic group from Italy and is in preclinical lead optimization [81][82][83][84][85][86].…”

Section: Small Molecules With Activity Against M Tuberculosismentioning

confidence: 99%

New Tuberculosis Drugs in Development

Laughon¹

2007

CTMC

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Over the past 50 years, no new drug classes have been introduced to treat tuberculosis. Tuberculosis (TB) kills nearly two million people a year mainly in the poorest communities in the developing world. It afflicts millions more. About one third of the world's population is silently infected with TB that may erupt into disease with increased age or suppression of the immune system. Nearly nine million new active cases develop every year. The World Health Organization (WHO) declared the disease a global emergency as long ago as 1993. Although huge efforts in public health control have reduced the disease burden within most established market economies, in Africa and Asia the epidemic continues to accelerate, particularly fueled by the HIV epidemic. Furthermore, resistance to the standard drugs isoniazid and rifampicin is increasing worldwide. Since the 1990s, mycobacteria have emerged with resistance patterns rendering all currently available antibiotics ineffectual. The pharmaceutical industry has mostly abandoned TB drug development due to perceived non-profitable consumer market and the diminishing number of companies engaged in anti-infective research. The public sector and infectious disease researchers have responded to advance fundamental science and to create new chemical entities as early drug candidates. With support from research funding agencies, philanthropic donors, and the STOP-TB Partnership, new chemical tools and new approaches to effectively implement TB control programs are evolving. Advanced preclinical development and strategies for Phase III clinical trials remain gap areas that will require additional engagement from all sectors.

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BM 212 and its Derivatives as a New Class of Antimycobacterial Active Agents

Cited by 26 publications

References 16 publications

MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212

MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212

New Small-Molecule Synthetic Antimycobacterials

New Tuberculosis Drugs in Development

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