Papers by Mahendra Chordia
Angewandte Chemie International Edition, Dec 14, 2023
The FEBS journal, 2018
Vibrio cholerae, the causative pathogen of the life-threatening infection cholera, encodes two co... more Vibrio cholerae, the causative pathogen of the life-threatening infection cholera, encodes two copies of b-ketoacyl-acyl carrier protein synthase III (vcFabH1 and vcFabH2). vcFabH1 and vcFabH2 are pathogenic proteins associated with fatty acid synthesis, lipid metabolism, and potential applications in biofuel production. Our biochemical assays characterize vcFabH1 as exhibiting specificity for acetyl-CoA and CoA thioesters with short acyl chains, similar to that observed for FabH homologs found in most gramnegative bacteria. vcFabH2 prefers medium chain-length acyl-CoA thioesters, particularly octanoyl-CoA, which is a pattern of specificity rarely seen in bacteria. Structural characterization of one vcFabH1 and six vcFabH2 structures determined in either apo form or in complex with acetyl-CoA/ octanoyl-CoA indicate that the substrate-binding pockets of vcFabH1 and vcFabH2 are of different sizes, accounting for variations in substrate chainlength specificity. An unusual and unique feature of vcFabH2 is its C-terminal fragment that interacts with both the substrate-entrance loop and the dimer interface of the enzyme. Our discovery of the pattern of substrate specificity of both vcFabH1 and vcFabH2 can potentially aid the development of novel antibacterial agents against V. cholerae. Additionally, the distinctive substrate preference of FabH2 in V. cholerae and related facultative anaerobes conceivably make it an attractive component of genetically engineered bacteria used for commercial biofuel production.
Journal of American Heart Association, 2023
BACKGROUND: Cardiac metabolic abnormalities are present in heart failure. Few studies have follow... more BACKGROUND: Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR).
Journal of the American Heart Association, May 16, 2023
Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followe... more Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose positron emission tomography in vivo in 9‐, 12‐, and 18‐month‐old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9‐month‐old SHR decreasing) 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12‐month‐old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.
bioRxiv (Cold Spring Harbor Laboratory), Oct 12, 2022
The general lack of permeability of small molecules observed for Mycobacterium tuberculosis (Mtb)... more The general lack of permeability of small molecules observed for Mycobacterium tuberculosis (Mtb) is most commonly ascribed to its unique cell envelope. More specifically, the outer mycomembrane is hypothesized to be the principal determinant for access of antibiotics to their molecular targets. Nonetheless, there is limited information on the types of molecular scaffolds that can readily permeate past the mycomembrane of mycobacteria. To address this, we describe a novel assay that combines metabolic tagging of the peptidoglycan scaffold, which sits directly beneath the mycomembrane, and a fluorescent labeling chase step, to measure the permeation of small molecules. We showed that the assay workflow was robust and compatible with high-throughput analysis in Mycobacterium smegmatis and Mtb. A small panel of molecules was tested and we found a large range in the permeability profile of molecules. Interestingly, the general trend is similar across the two types of mycobacteria, with some notable exceptions. We anticipate that this assay platform will lay the foundation for medicinal chemistry efforts to understand and improve uptake of both existing drugs and newly-discovered compounds into mycobacteria. The methods described, which do not require genetic manipulation, can be generally adopted to other species for which envelope permeability is treatment-limiting.
ChemInform, Jun 14, 2010
ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)über... more ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)übergeführt, die Wirkung gegen Leukämiezellen der Maus besitzen. Am wirksamsten ist die Verbindung (IIIa). (UV-spektroskopische Daten).
ChemInform, Aug 19, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Open journal of synthesis theory and applications, 2013
The triterpene quassinoid ailanthinone is a structurally intricate natural product possessing hig... more The triterpene quassinoid ailanthinone is a structurally intricate natural product possessing highly potent antimalarial activity against multidrug resistance plasmodium parasites. Although the mechanism of action of ailanthinone is not completely understood, it is presumed to disrupt regular ribosomal functions by inhibiting parasite protein synthesis. Natural scarcity and low solubility of many quassinoids have impeded their development as potential clinical candidates, but exquisite potency of ailanthinone against Plasmodium remains compelling in the global fight against malaria. Herein, we report the highly selective synthesis of 1-hydroxyl derivatives of ailanthinone, including ester, carbonate, carbamate and sulfonate derivatives. The key feature of the synthesis is a one-step regioselective modification of the 1-hydroxyl group in favor of two other hydroxyl groups at C12 and C13. Derivatives were obtained via direct reaction with acyl/sulfonyl chlorides in the presence of a tertiary amine base without any protection-deprotection. In vitro antimalarial evaluations of these derivatives were compared with chloroquine and mefloquine against the Plasmodium falciparum clones, D6, W2, and TM91C235. The results demonstrate that modification of the 1-hydroxyl group is achievable, and the antimalarial activity of these derivatives relative to the parent product is significantly retained, thus paving the way for synthesis of derivatives with improved biological availability and/or increased potency.
bioRxiv (Cold Spring Harbor Laboratory), May 5, 2022
In mammals, gut commensal microbiota interact extensively with the host and the same interactions... more In mammals, gut commensal microbiota interact extensively with the host and the same interactions can be dysregulated in diseased states. The development of methods to monitor gut microbiota in vivo can lead to improved foundational understanding of the biological events underpinning these interactions. The current standard for non-invasive monitoring of gut bacteria entails classification by 16S rRNA sequencing from fecal samples. This method has many advantages but also has serious limitations, especially for monitoring dynamic changes in the gut of live animals. In recent years, several imaging techniques have been widely adopted that afford non-invasive assessment of animal subjects-most notably in cancer biology; however, these technical gains have not translated to the imaging of gut bacterial communities. Herein, we describe a method to non-invasively image commensal bacteria based on the specific metabolic labeling of bacterial cell walls to illuminate the gut bacteria of live mice. This tagging strategy may additionally provide unprecedented insight into cell wall turnover of gut commensals, which has implications for bacterial cellular growth and division, in a live animal.
Tetrahedron, Apr 1, 1997
... Printed in Great Britain 00404020 97 17.00 + 0.00 Synthesis and Biological Evaluation of Amid... more ... Printed in Great Britain 00404020 97 17.00 + 0.00 Synthesis and Biological Evaluation of AmideLinked A Norpaclitaxels Mahendra D. Chordia and David GI Kingston* Department of Chemistry, Virginia Polytechnic ... Samaranayake, G.; Magri, NF; Jitrangsri, C.; Kingston, DGIJ Org ...
ChemInform, Aug 3, 2010
ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)über... more ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)übergeführt, die Wirkung gegen Leukämiezellen der Maus besitzen. Am wirksamsten ist die Verbindung (IIIa). (UV-spektroskopische Daten).
ChemInform, Jun 7, 2010
Asymmetric Dearomatization of η 2-Arene Complexes: Synthesis of Stereodefined Functionalized Cycl... more Asymmetric Dearomatization of η 2-Arene Complexes: Synthesis of Stereodefined Functionalized Cyclohexenones and Cyclohexenes.-A simple chiral auxiliary (lactate) attached to an arene is used to direct the stereospecific coordination to pentaammineosmium(II) [complex (I)]. It thereby induces high transfer of chirality to C-4, C-3, and C-1 of the arene as well at the benzylic position at C-4, to yield after further elaborations substituted cyclohexenones such as (VII), cis-trisubstituted cyclohexenes such as (X), cyclohexenes such as (XVII) and rearomatized derivatives (XIII), derived from intermediate 4H-oxonium complexes. It is found that a bulky isopropyl group at the alkoxy chiral auxiliary in complex (XVIII) leads to a more complete transfer of chirality. The essential feature of the presented strategy is that the chiral auxiliary directly interacts only with the metal, and not with the chemical reagents, so that the degree of stereoselectivity is not a function of the interaction between chiral auxiliary and reagent.-(CHORDIA,
ChemInform, Aug 23, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Journal of the American Chemical Society, Jun 14, 1998
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Papers by Mahendra Chordia