Gyanu lamichhane biography template
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A Pivotal Role for Mycobactin/mbtE in Growth and Adaptation of Mycobacterium abscessus
ABSTRACT
Mycobacterium abscessus is an emerging pathogen that critically depends on iron for growth and pathogenesis. The acquisition of iron in Mycobacterium tuberculosis is governed by siderophores called mycobactins, synthesized by the mbt gene cluster, but the role of this gene cluster in the adaption of M. abscessus to iron limitation is not characterized. We identified an M. abscessus Tn_mutant with interruption of the mbtE gene (MAB_2248c), a central component of mycobactin biosynthesis. We tested this isolate growth characteristic, dependency on supplements, and transcriptomic response, comparing it to the response of wild-type (WT) bacteria in iron-limiting conditions. We also compare the structure of the mbt gene cluster across several mycobacteria. The Tn_mbtE mutant had a substantial, but not absolute, growth defect, which was more substantial in iron-limited m
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Abstract
L,D-transpeptidase function predominates in atypical 3 → 3 transpeptide networking of peptidoglycan (PG) layer in Mycobacterium tuberculosis. Prior studies of L,D-transpeptidases have identified only the catalytic site that binds to peptide moiety of the PG substrate or β-lactam antibiotics. This insight was leveraged to develop mechanism of its activity and inhibition by β-lactams. Here, we report identification of an allosteric site at a distance of 21 Å from the catalytic site that binds the sugar moiety of PG substrates (hereafter referred to as the S-pocket). This site also binds a second β-lactam molecule and influences binding at the catalytic site. We provide evidence that two β-lactam molecules bind co-operatively to this enzyme, one non-covalently at the S-pocket and one covalently at the catalytic site. This dual β-lactam-binding phenomenon is previously unknown and is an observation that may offer novel approaches for the structure-based design of new drugs
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Open Access
Peer-reviewed
- Ravindra Jadhav,
- Ricardo Gallardo-Macias,
- Gaurav Kumar,
- Samer S. Daher,
- Amit Kaushik,
- Kristina M. Bigelow,
- Eric L. Nuermberger ,
- Gyanu Lamichhane ,
- Joel S. Freundlich
Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing
* E-mail:freundjs@rutgers.edu (JSF); gyanu@jhu.edu (GL); enuermb@jhmi.edu (ELN)
Affiliations Department of Pharmacology, Physiology, and Neuroscience, Rutgers University–New Jersey Medical School, Newark, New Jersey, United States of America, Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University—New Jersey Medical School, Newark, New Jersey, United States of America
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- Ravindra Jadhav,
- Ricardo Gallardo-Macias