Structural basis for the inhibition of<i>Mycobacterium tuberculosis</i><scp>L</scp>,<scp>D</scp>-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains

Kim, Hyoun Sook; Kim, Jieun; Im, Ha Na; Yoon, Ji Young; An, Doo Ri; Yoon, Hye Jin; Kim, Jin Young; Min, Hye Kyeoung; Kim, Soon-Jong; Lee, Jae Young; Han, Byung Woo; Suh, Se Won

doi:10.1107/s0907444912048998

Cited by 70 publications

(116 citation statements)

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“…The crystal structure of Ldt Mt2 was recently reported by four independent groups (19)(20)(21)(22). These studies also report molecular interactions with the substrate and the carbapenem class of drugs and the mechanism of catalysis by Ldt Mt2 .…”

Section: Discussionmentioning

confidence: 73%

“…Although ␤-lactams are rarely used for treatment of M. tuberculosis infection, recent reports demonstrate that the carbapenem subclass of ␤-lactams are effective against a range of M. tuberculosis strains (44)(45)(46). Although certain carbapenems have been demonstrated to bind to and inhibit L,D-transpeptidase activity (19,(21)(22)(23), it is not known if their M. tuberculosis growthinhibitory activity is a result of inhibition of specific or multiple transpeptidases. The in vivo study demonstrated that loss of ldt Mt1 and ldt Mt2 makes M. tuberculosis uniquely susceptible when exposed to a combination of amoxicillin-clavulanate and vancomycin.…”

Section: Discussionmentioning

confidence: 99%

“…While biochemical properties and the contribution of Ldt Mt2 to the physiology of M. tuberculosis have been reported (16,(19)(20)(21)(22), studies of Ldt Mt1 have been limited to biochemical characterization (6,23). In this study, for the first time, we have generated and studied M. tuberculosis strains lacking Ldt Mt1 and both Ldt Mt1 and Ldt Mt2 and describe the cellular phenotypes associated with the loss of these L,D-transpeptidases.…”

mentioning

confidence: 99%

“…Despite the significance of D,D-transpeptidases, which serve as targets to the most widely used class of antibiotics, the study of the relevance of L,D-transpeptidases to the physiology of the cell and susceptibility to drugs has only recently begun. Within 6 months following the first report describing the crystal structure and mechanism of L,Dtranspeptidation by Ldt Mt2 (19), four additional reports describing structural details of L,D-transpeptidases of M. tuberculosis were published (20)(21)(22)(23).…”

mentioning

confidence: 99%

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Nonclassical Transpeptidases of Mycobacterium tuberculosis Alter Cell Size, Morphology, the Cytosolic Matrix, Protein Localization, Virulence, and Resistance to β-Lactams

2014

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T he peptidoglycan layer is present in virtually all bacteria and is essential for its survival and growth. This layer is classically described as a structural component that is assembled outside the membrane, that is largely cross-linked by 4¡3 transpeptide linkages, and that gives shape and turgidity to the cell but otherwise is not dynamic (1). Based on this paradigm of peptidoglycan biology, 3¡3 transpeptide linkages observed in Mycobacterium spp. and Escherichia coli were considered unusual and were speculated to be modifications or derivatives of 4¡3 linkages (2-5). Recent studies have demonstrated that the peptidoglycan layer of Mycobacterium spp. is largely cross-linked by 3¡3 transpeptide linkages (6-8). A significant effort was made to identify L,D-transpeptidases based on the hypothesis that they may be close sequence homologs of D,D-transpeptidases (9, 10). In E. coli, altered growth rates and susceptibility to ␤-lactams have been reported in relation to changes in the composition of 3¡3 linkages in the peptidoglycan (4, 11). An increase in the proportion of 3¡3 transpeptide linkages reduces growth rates and subsequently decreases the susceptibility of E. coli to ␤-lactams.Inhibition of the biosynthesis of the peptidoglycan layer has been successfully exploited, as drugs that target this layer are the most widely used antibiotics to treat bacterial infections in humans. ␤-Lactams, a class of drugs that inhibit peptidoglycan biosynthesis, comprise more than half of all antibiotics regularly prescribed to treat bacterial infections (12). The ␤-lactams act by inhibiting D,D-transpeptidases (also known as penicillin-binding proteins), a class of enzymes that catalyze the formation of transpeptide linkages between the fourth amino acid of one peptide stem and the third amino acid of another stem. Recently, a complementary class of enzymes, namely, L,D-transpeptidases, that transfer peptide linkage between the L and D centers of the third and the fourth amino acids of donor peptide to the third amino acid of acceptor peptide has been identified in numerous bacteria, including Enterococcus faecium, Bacillus subtilis, Mycobacterium tuberculosis, Clostridium difficile, and E. coli (6,(13)(14)(15)(16)(17)(18). Despite the significance of D,D-transpeptidases, which serve as targets to the most widely used class of antibiotics, the study of the relevance of L,D-transpeptidases to the physiology of the cell and susceptibility to drugs has only recently begun. Within 6 months following the first report describing the crystal structure and mechanism of L,Dtranspeptidation by Ldt Mt2 (19), four additional reports describing structural details of L,D-transpeptidases of M. tuberculosis were published (20-23).The M. tuberculosis genome encodes as many as five proteins with L,D-transpeptidase activity, namely, Ldt Mt1 to Ldt Mt5 (6,16,24). While biochemical properties and the contribution of Ldt Mt2 to the physiology of M. tuberculosis have been reported (16,(19)(20)(21)(22), studies of Ldt Mt1 have been limited to bioc...

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Nonclassical Transpeptidases of Mycobacterium tuberculosis Alter Cell Size, Morphology, the Cytosolic Matrix, Protein Localization, Virulence, and Resistance to β-Lactams

2014

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“…It has been demonstrated that ␤-lactams interfere with peptidoglycan biosynthesis and metabolism in multiple ways and eventually results in cell death (17,19). Among ␤-lactams, carbapenems and penems are able to bind and inhibit activities of D,D-transpeptidases, L,D-transpeptidases, and D,D-carboxypeptidases (6,(20)(21)(22)(23)(24)(25)(26). This versatile property of (carba)penems to target multiple enzymes prompted the current study to test the clinical utility of commercially available (carba) penems in M. tuberculosis and M. abscessus isolates from patients.…”

Section: Discussionmentioning

confidence: 99%

Carbapenems and Rifampin Exhibit Synergy against Mycobacterium tuberculosis and Mycobacterium abscessus

Kaushik

Makkar

Pandey

et al. 2015

Antimicrob Agents Chemother

109

113

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cAn effective regimen for treatment of tuberculosis (TB) is comprised of multiple drugs that inhibit a range of essential cellular activities in Mycobacterium tuberculosis. The effectiveness of a regimen is further enhanced if constituent drugs act with synergy. Here, we report that faropenem (a penem) or biapenem, doripenem, or meropenem (carbapenems), which belong to the ␤-lactam class of antibiotics, and rifampin, one of the drugs that forms the backbone of TB treatment, act with synergy when combined. One of the reasons (carba)penems are seldom used for treatment of TB is the high dosage levels required, often at the therapeutic limits. The synergistic combination of rifampin and these (carba)penems indicates that (carba)penems can be administered at dosages that are therapeutically relevant. The combination of faropenem and rifampin also limits the frequency of resistant mutants, as we were unable to obtain spontaneous mutants in the presence of these two drugs. The combinations of rifampin and (carba)penems were effective not only against drug-sensitive Mycobacterium tuberculosis but also against drugresistant clinical isolates that are otherwise resistant to rifampin. A combination of doripenem or biapenem and rifampin also exhibited synergistic activity against Mycobacterium abscessus. Although the MICs of these three drugs alone against M. abscessus are too high to be of clinical relevance, their concentrations in combinations are therapeutically relevant; therefore, they warrant further evaluation for clinical utility to treat Mycobacterium abscessus infection, especially in cystic fibrosis patients.

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Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations

Moreira

Ramos

Fernandes

2016

Chemistry A European J

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This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1) , which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1) ). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies.

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Structural basis for the inhibition ofMycobacterium tuberculosisL,D-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains

Abstract: The crystal structure of M. tuberculosis l,d-transpeptidase (LdtMt2; Rv2518c) has been determined in both ligand-free and meropenem-bound forms. The detailed view of the interactions between meropenem and LdtMt2 will be useful in structure-guided discovery of new antituberculosis drugs.

Cited by 70 publications

References 38 publications

Nonclassical Transpeptidases of Mycobacterium tuberculosis Alter Cell Size, Morphology, the Cytosolic Matrix, Protein Localization, Virulence, and Resistance to β-Lactams

Nonclassical Transpeptidases of Mycobacterium tuberculosis Alter Cell Size, Morphology, the Cytosolic Matrix, Protein Localization, Virulence, and Resistance to β-Lactams

Carbapenems and Rifampin Exhibit Synergy against Mycobacterium tuberculosis and Mycobacterium abscessus

Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations

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