Structure and function of the Mur enzymes: development of novel inhibitors

Zoeiby, Ahmed El; Sanschagrin, François; Levesque, Roger C.

doi:10.1046/j.1365-2958.2003.03289.x

Cited by 297 publications

(224 citation statements)

References 71 publications

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“…This enzyme, encoded by an essential gene in bacteria, is involved in an early step of peptidoglycan synthesis (El Zoeiby et al, 2003). IS1548 insertion upstream of murB was found to be widespread among CC19 clinical strains, suggesting a possible role in bacterial pathogenicity (Fléchard et al, 2013a).…”

Section: Mobile Genetic Element Of the Isas1 Familymentioning

confidence: 99%

Physiological impact of transposable elements encoding DDE transposases in the environmental adaptation of Streptococcus agalactiae

Fléchard

Gilot

2014

Microbiology

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We have referenced and described Streptococcus agalactiae transposable elements encoding DDE transposases. These elements belonged to nine families of insertion sequences (ISs) and to a family of conjugative transposons (TnGBSs). An overview of the physiological impact of the insertion of all these elements is provided. DDE-transposable elements affect S. agalactiae in a number of aspects of its capability to adapt to various environments and modulate the expression of several virulence genes, the scpB-lmB genomic region and the genes involved in capsule expression and haemolysin transport being the targets of several different mobile elements. The referenced mobile elements modify S. agalactiae behaviour by transferring new gene(s) to its genome, by modifying the expression of neighbouring genes at the integration site or by promoting genomic rearrangements. Transposition of some of these elements occurs in vivo, suggesting that by dynamically regulating some adaptation and/or virulence genes, they improve the ability of S. agalactiae to reach different niches within its host and ensure the 'success' of the infectious process.

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Section: Mobile Genetic Element Of the Isas1 Familymentioning

confidence: 99%

Physiological impact of transposable elements encoding DDE transposases in the environmental adaptation of Streptococcus agalactiae

Fléchard

Gilot

2014

Microbiology

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“…A high-energy tetrahedral intermediate is formed, which eventually collapses to yield UDP-MurNAc-L-Ala-D-Glu, ADP, and inorganic phosphate [11]. High specificity, ubiquity among bacteria, and absence in mammals make MurD a promising target for antibacterial therapy [12].…”

Section: Introductionmentioning

confidence: 99%

Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

2010

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The life-threatening infections caused by Leptospira serovars remain a global challenge since long time. Prevention of infection by controlling environmental factors being difficult to practice in developing countries, there is a need for designing potent anti-leptospirosis drugs. ATP-dependent MurD involved in biosynthesis of peptidoglycan was identified as common drug target among pathogenic Leptospira serovars through subtractive genomic approach. Peptidoglycan biosynthesis pathway being unique to bacteria and absent in host represents promising target for antimicrobial drug discovery. Thus, MurD 3D models were generated using crystal structures of 1EEH and 2JFF as templates in Modeller9v7. Structural refinement and energy minimization of the model was carried out in Maestro 9.0 applying OPLS-AA 2001 force field and was evaluated through Procheck, ProSA, PROQ, and Profile 3D. The active site residues were confirmed from the models in complex with substrate and inhibitor. Four published MurD inhibitors (two phosphinics, one sulfonamide, and one benzene 1,3-dicarbixylic acid derivative) were queried against more than one million entries of Ligand.Info Meta-Database to generate in-house library of 1,496 MurD inhibitor analogs. Our approach of virtual screening of the best-ranked compounds with pharmacokinetics property prediction has provided 17 novel MurD inhibitors for developing anti-leptospirosis drug targeting peptidoglycan biosynthesis pathway.

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“…Indeed, the first step during PG biosynthesis is the conversion of UDP-GlcNAc to UDP-MurNAc. 32 Lysozymes (muramidases) (EC 3.2.1.17), are glycoside hydrolases that cleave the β-1,4 linkages in murein, causing bacterial cell lysis, as first observed by Alexander Fleming. 33 Besides their direct bacteriolytic action, these proteins also have an immunomodulatory function in the host's response to infection.…”

Section: Discussionmentioning

confidence: 99%