@article {48235,
	title = {Kupyaphores are zinc homeostatic metallophores required for colonization of Mycobacterium tuberculosis},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {119},
	year = {2022},
	month = {FEB},
	pages = {e2110293119},
	type = {Article},
	abstract = {<p>
	Mycobacterium tuberculosis (Mtb) endures a combination of metal scarcity and toxicity throughout the human infection cycle, contributing to complex clinical manifestations. Pathogens counteract this paradoxical dysmetallostasis by producing specialized metal trafficking systems. Capture of extracellular metal by siderophores is a widely accepted mode of iron acquisition, and Mtb iron-chelating siderophores, mycobactin, have been known since 1965. Currently, it is not known whether Mtb produces zinc scavenging molecules. Here, we characterize low-molecular-weight zinc-binding compounds secreted and imported by Mtb for zinc acquisition. These molecules, termed kupyaphores, are produced by a 10.8 kbp biosynthetic cluster and consists of a dipeptide core of ornithine and phenylalaninol, where amino groups are acylated with isonitrilecontaining fatty acyl chains. Kupyaphores are stringently regulated and support Mtb survival under both nutritional deprivation and intoxication conditions. A kupyaphore-deficient Mtb strain is unable to mobilize sufficient zinc and shows reduced fitness upon infection. We observed early induction of kupyaphores in Mtb-infected mice lungs after infection, and these metabolites disappeared after 2 wk. Furthermore, we identify an Mtb-encoded isonitrile hydratase, which can possibly mediate intracellular zinc release through covalent modification of the isonitrile group of kupyaphores. Mtb clinical strains also produce kupyaphores during early passages. Our study thus uncovers a previously unknown zinc acquisition strategy of Mtb that could modulate host-pathogen interactions and disease outcome.</p>
},
	keywords = {metallophore, nutritional immunity, tuberculosis, zinc},
	issn = {0027-8424},
	doi = {10.1073/pnas.2110293119},
	author = {Mehdiratta, Kritee and Singh, Shubham and Sharma, Sachin and Bhosale, Rashmi S. and Choudhury, Rahul and Masal, Dattatraya P. and Manocha, Alzu and Dhamale, Bhushan Dilip and Khan, Naseem and Asokachandran, Vivekanand and Sharma, Pooja and Ikeh, Melanie and Brown, Amanda C. and Parish, Tanya and Ojha, Anil K. and Michael, Joy Sarojini and Faruq, Mohammed and Medigeshi, Guruprasad R. and Mohanty, Debasisa and Reddy, D. Srinivasa and Natarajan, Vivek T. and Kamat, Siddhesh S. and Gokhale, Rajesh S.}
}
@article {48826,
	title = {Synthesis, biological evaluation and docking studies of silicon incorporated diarylpyrroles as MmpL3 inhibitors: an effective strategy towards development of potent anti-tubercular agents},
	journal = {European Journal of Medicinal Chemistry},
	volume = {259},
	year = {2023},
	month = {NOV },
	pages = {115633},
	type = {Article},
	abstract = {<p>
	Growing global demand for new molecules to treat tuberculosis has created an urgent need to develop novel strategies to combat the menace. BM212 related compounds were found to be potent anti-TB agents and they inhibit mycolic acid transporter, MmpL3, a known potent drug target from Mycobacterium tuberculosis. In order to enhance their inhibitory potency, several silicon analogues of diarylpyrroles related to BM212 were designed, synthesized, and evaluated for anti-tubercular activities. In Alamar blue assay, most of the silicon-incorporated compounds were found to be more potent than the parent compound (BM212), against Mycobacterium tuberculosis (MIC = 1.7 \&amp; mu;M, H37Rv). Docking results from the crystal structure of MmpL3 and silicon analogues as pharmacophore model also strongly correlate with the biological assays and suggest that the incorporation of silicon in the inhibitor scaffold could enhance their potency by stabilizing the hydrophobic residues at the binding pocket. The best docking hit, compound 12 showed an MIC of 0.1 \&amp; mu;M against H37Rv with an acceptable in vitro ADME profile and excellent selectivity index. Overall, the present study indicates that, the designed silicon analogues, especially compound 12 could be a good inhibitor for an intrinsically flexible drug-binding pocket of MmpL3 and has potential for further development as anti-tubercular agents.</p>
},
	keywords = {antibiotic, BM212, docking studies, MmpL3 inhibitor, Silicon analogue, tuberculosis},
	issn = {0223-5234},
	doi = {10.1016/j.ejmech.2023.115633},
	author = {Vasudevan, N. and Motiwala, Zenia and Ramesh, Remya and Wagh, Sachin B. and Shingare, Rahul D. and Katte, Revansiddha and Anand, Amitesh and Choudhary, Sushil and Kumar, Ajay and Gokhale, Rajesh S. and Kulkarni, Kiran A. and Reddy, D. Srinivasa}
}
