Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors

Siricilla, Shajila; Mitachi, Katsuhiko; Wan, Bajoie; Franzblau, Scott G.; Kurosu, Masaaki

doi:10.1038/ja.2014.133

Cited by 58 publications

(63 citation statements)

References 41 publications

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“…7-11,13,21 What was not known prior to this effort, however, was whether substituting for the l -ACL had any effect on the activity of the hexuronic acid phosphotransferase, which we previously established is a mechanism of self-resistance by the producing strain. 16,17 A similar phenomenon is found within aminoglycoside producing strains that often encode for phosphotransferases to covalently modify and inactivate the self-made antibacterial product, and it has been established that identical mechanisms—often acquired through horizontal gene transfer—are employed by pathogens to render these antibiotics inactive.…”

Section: Discussionmentioning

confidence: 99%

A biocatalytic approach to capuramycin analogues by exploiting a substrate permissive N-transacylase CapW

et al. 2016

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Using the ATP-independent transacylase CapW required for the biosynthesis of capuramycin-type antibiotics, we developed a biocatalytic approach for the synthesis of 43 analogues via a one-step aminolysis reaction from the methyl ester precursor as the acyl donor and various nonnative amines as acyl acceptors. Further examination of the donor substrate scope for CapW revealed this enzyme can also catalyze a direct transamidation reaction using the major capuramycin congener as a semisynthetic precursor. Biological activity tests revealed that a few of the new capuramycin analogues have significantly improved antibiotic activity against Mycobacterium smegmatis MC2 155 and Mycobacterium tuberculosis H37Rv. Furthermore, most of the analogues are able to be covalently modified by the phosphotransferase CapP/Cpr17 involved in self resistance, providing critical insight for future studies regarding clinical development of the capuramycin antimycobacterial antibiotics.

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Section: Discussionmentioning

confidence: 99%

A biocatalytic approach to capuramycin analogues by exploiting a substrate permissive N-transacylase CapW

et al. 2016

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“…Due to attrition of drugs during the development pipeline, large-scale screening is necessary to allow prioritization of scaffolds with properties amenable to synthesis and medicinal chemistry optimization. A few recent studies have used nonreplicating M. tuberculosis to test small numbers of samples (45,46). These small-scale reports illustrate the potential of naturally derived compounds against nonreplicating M. tuberculosis and highlight the need for larger-scale screens of natural products under these conditions.…”

Section: Discussionmentioning

confidence: 99%

Selective Killing of Dormant Mycobacterium tuberculosis by Marine Natural Products

Felix

Gupta

Geden

et al. 2017

Antimicrob Agents Chemother

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The dormant phenotype acquired by Mycobacterium tuberculosis during infection poses a major challenge in disease treatment, since these bacilli show tolerance to front-line drugs. Therefore, it is imperative to find novel compounds that effectively kill dormant bacteria. By screening 4,400 marine natural product samples against dual-fluorescent M. tuberculosis under both replicating and nonreplicating conditions, we have identified compounds that are selectively active against dormant M. tuberculosis. This validates our strategy of screening all compounds in both assays as opposed to using the dormancy model as a secondary screen. Bioassayguided deconvolution enabled the identification of unique pharmacophores active in each screening model. To confirm the activity of samples against dormant M. tuberculosis, we used a luciferase reporter assay and enumerated CFU. The structures of five purified active compounds were defined by nuclear magnetic resonance (NMR) and mass spectrometry. We identified two lipid compounds with potent activity toward dormant and actively growing M. tuberculosis strains. One of these was commercially obtained and showed similar activity against M. tuberculosis in both screening models. Furthermore, puupehenone-like molecules were purified with potent and selective activity against dormant M. tuberculosis. In conclusion, we have identified and characterized antimycobacterial compounds from marine organisms with novel activity profiles which appear to target M. tuberculosis pathways that are conditionally essential for dormancy survival.

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“…Lesser potent capuramycin analogues include SQ997 and SQ922. Another capuramycin ana-logue, UT-01320 inhibiting RNA polymerase was found to be effective against dormant mycobacteria and showed synergism with SQ-641 [64]. Quinolones with varied substitutions are being developed and tested against TB bacilli.…”

Section: Molecules In Preclinical Study Phasementioning

confidence: 98%

Newer Patents in Antimycobacterial Therapy

Sk¹

2015

Pharm. Pat. Anal.

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Tuberculosis caused by Mycobacterium tuberculosis is a global health emergency. This deadly disease has far-reaching social and economic implications. Diseased individuals need prolonged polypharmacy which is not without ill effects. Treatment compliance is often compromised contributing to rising resistance. HIV co-infection has further worsened the scenario. On the other hand, no new anti-TB drug has hit the market in last 4-5 decades. After a long latency, only the last few years have witnessed growing research in this direction and a widening anti-TB drug clinical pipeline. The compounds in preclinical stage of development have also shown a heartening increase. The present review is an attempt to discuss novel promising patents in this field.

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Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors

Cited by 58 publications

References 41 publications

A biocatalytic approach to capuramycin analogues by exploiting a substrate permissive N-transacylase CapW

A biocatalytic approach to capuramycin analogues by exploiting a substrate permissive N-transacylase CapW

Selective Killing of Dormant Mycobacterium tuberculosis by Marine Natural Products

Newer Patents in Antimycobacterial Therapy

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