Meropenem inhibits <scp>D</scp>,<scp>D</scp>‐carboxypeptidase activity in <i><scp>M</scp>ycobacterium tuberculosis</i>

Kumar, Pradeep; Arora, Kriti; Lloyd, John R.; Lee, Ill Young; Nair, Vinod; Fischer, Elizabeth R.; Boshoff, Helena I.; Barry, Clifton E.

doi:10.1111/j.1365-2958.2012.08199.x

Cited by 133 publications

(175 citation statements)

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“…This may indicate that new glycan strands (synthesized by PonA1 or PonA2) are predominantly first cross-linked in a 3-3 manner (for example, by LdtB). This model is supported by the prevalence of 3-3 crosslinks in mycobacterial PG at all growth stages (5). Our data also show that LdtB is critical for the maintenance of normal cell shape (Fig.…”

Section: Discussionsupporting

confidence: 71%

“…S7). Whereas bifunctional PBPs are critical in many bacterial species (3), mycobacterial PG exhibits very different architecture with its prevalence of 3-3 cross-links (4,5). Using allelic exchange, we found that only tiny ΔponA1 ΔldtB colonies could be seen after 21 d of growth, when ΔldtB colonies were already large ( Fig.…”

Section: Ldtb Is Critical For Normal Bacterial Fitness In Cells Withomentioning

confidence: 88%

“…The abundance of 3-3 cross-links in mycobacterial PG throughout different growth stages (5) suggests that Ldts are…”

mentioning

confidence: 99%

“…1A]. The predominant peptide cross-links in mycobacteria join the third amino acids (3-3 link) of adjacent stem peptides (4,5), which are synthesized by L,D-transpeptidases (Ldts) such as LdtB, one of the major Ldts in Mtb (Fig. 1A).…”

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confidence: 99%

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Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility

Kieser

Baranowski

Chao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Peptidoglycan (PG), a complex polymer composed of saccharide chains cross-linked by short peptides, is a critical component of the bacterial cell wall. PG synthesis has been extensively studied in model organisms but remains poorly understood in mycobacteria, a genus that includes the important human pathogen Mycobacterium tuberculosis (Mtb). The principle PG synthetic enzymes have similar and, at times, overlapping functions. To determine how these are functionally organized, we carried out whole-genome transposon mutagenesis screens in Mtb strains deleted for ponA1, ponA2, and ldtB, major PG synthetic enzymes. We identified distinct factors required to sustain bacterial growth in the absence of each of these enzymes. We find that even the homologs PonA1 and PonA2 have unique sets of genetic interactions, suggesting there are distinct PG synthesis pathways in Mtb. Either PonA1 or PonA2 is required for growth of Mtb, but both genetically interact with LdtB, which has its own distinct genetic network. We further provide evidence that each interaction network is differentially susceptible to antibiotics. Thus, Mtb uses alternative pathways to produce PG, each with its own biochemical characteristics and vulnerabilities.Mycobacterium tuberculosis | transposon sequencing | genetic interaction | peptidoglycan | cell wall

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Section: Discussionsupporting

confidence: 71%

Section: Ldtb Is Critical For Normal Bacterial Fitness In Cells Withomentioning

confidence: 88%

“…The abundance of 3-3 cross-links in mycobacterial PG throughout different growth stages (5) suggests that Ldts are…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility

Kieser

Baranowski

Chao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies have demonstrated that the peptidoglycan layer of Mycobacterium spp. is largely cross-linked by 3¡3 transpeptide linkages (6)(7)(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).…”

mentioning

confidence: 99%

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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Synthesis of Avibactam Derivatives and Activity on β‐Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria

Edoo

Iannazzo

Compain

et al. 2018

Chemistry A European J

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There is a renewed interest for β-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their β-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen-Sharpless cycloaddition reaction is reported. The amoxicillin-DBO combinations were active, indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 μg mL for both species). Mechanistically, β-lactamase inhibition was not sufficient to account for the potentiation of amoxicillin by DBOs. Thus, the latter compounds were investigated as inhibitors of l,d-transpeptidases (Ldts), which are the main peptidoglycan polymerases in mycobacteria. The DBOs acted as slow-binding inhibitors of Ldts by S-carbamoylation indicating that optimization of DBOs for Ldt inhibition is an attractive strategy to obtain drugs selectively active on mycobacteria.

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Meropenem inhibits D,D‐carboxypeptidase activity in Mycobacterium tuberculosis

Cited by 133 publications

References 50 publications

Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility

Peptidoglycan synthesis in Mycobacterium tuberculosis is organized into networks with varying drug susceptibility

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

Synthesis of Avibactam Derivatives and Activity on β‐Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria

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