Allosteric inhibition of
            <i>Staphylococcus aureus</i>
            <scp>d</scp>
            -alanine:
            <scp>d</scp>
            -alanine ligase revealed by crystallographic studies

Liu, Shenping; Chang, Jeanne S.; Herberg, John T.; Horng, Miao-Miao; Tomich, Paul K.; Lin, Alice H.; Marotti, Keith R.

doi:10.1073/pnas.0604905103

Cited by 80 publications

(88 citation statements)

References 27 publications

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“…Thus, the mode of inhibition of DDLA by salvicine was different from those previously reported inhibitors of DDLA such as phosphinate, phosphonate, and D-cycloserine where these inhibitors have been reported to act as competitive inhibitors for either substrate or cofactor (Liu et al, 2006). In agreement to our finding, Liu, et al, (2006), based on crystallographic analyses, have proposed an allosteric inhibition model for Staphylococcus aureus DDLA by the inhibitor 3-chloro-2,2-dimethyl-N-(4(trifluoromethyl)phenyl) propanamide. Although based on the screening of a natural products database of readily available compounds, pomiferin, a flavonoid was found to be the best, but on comparison, the terpenoid salvicine was found to be an even more efficient inhibitor of DDLA than pomiferin.…”

Section: Discussionmentioning

confidence: 41%

“…These enzyme/proteins were selected on the basis of their role in the survival of the pathogen. Many of these targets have been reported as potential drug targets in several other bacteria [e.g, Neisseria gonorrhoeae , Mycobacterium tuberculosis (Bruning et al, 2010), Staphylococcus aureus (Liu et al, 2006)]. Thus, the enzyme protein UDPN of the peptidoglycan biosynthesis pathway has been analyzed as an antibacterial drug target (Gu et al, 2004;Lovering et al, 2012;Steven, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Treponema pallidumPutative Novel Drug Target Identification and Validation: Rethinking Syphilis Therapeutics with Plant-Derived Terpenoids

Dwivedi

Tiwari

Singh

et al. 2015

OMICS: A Journal of Integrative Biology

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Syphilis, a slow progressive and the third most common sexually transmitted disease found worldwide, is caused by a spirochete gram negative bacteria Treponema pallidum. Emergence of antibiotic resistant T. pallidum has led to a search for novel drugs and their targets. Subtractive genomics analyses of pathogen T. pallidum and host Homo sapiens resulted in identification of 126 proteins essential for survival and viability of the pathogen. Metabolic pathway analyses of these essential proteins led to discovery of nineteen proteins distributed among six metabolic pathways unique to T. pallidum. One hundred plant-derived terpenoids, as potential therapeutic molecules against T. pallidum, were screened for their drug likeness and ADMET (absorption, distribution, metabolism, and toxicity) properties. Subsequently the resulting nine terpenoids were docked with five unique T. pallidum targets through molecular modeling approaches. Out of five targets analyzed, D-alanine:D-alanine ligase was found to be the most promising target, while terpenoid salvicine was the most potent inhibitor. A comparison of the inhibitory potential of the best docked readily available natural compound, namely pomiferin (flavonoid) with that of the best docked terpenoid salvicine, revealed that salvicine was a more potent inhibitor than that of pomiferin. To the best of our knowledge, this is the first report of a terpenoid as a potential therapeutic molecule against T. pallidum with D-alanine:D-alanine ligase as a novel target. Further studies are warranted to evaluate and explore the potential clinical ramifications of these findings in relation to syphilis that has public health importance worldwide.

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Section: Discussionmentioning

confidence: 41%

Section: Discussionmentioning

confidence: 99%

Treponema pallidumPutative Novel Drug Target Identification and Validation: Rethinking Syphilis Therapeutics with Plant-Derived Terpenoids

Dwivedi

Tiwari

Singh

et al. 2015

OMICS: A Journal of Integrative Biology

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“…Nucleotide Binding Site-As reported for other D-Ala:D-X ligases (13)(14)(15), the nucleotide binding site is formed by two antiparallel ␤-sheets from the central and C-terminal domains. The position and orientation of ADP in the binding site are highly conserved.…”

Section: Resultsmentioning

confidence: 99%

“…Kinetic studies have identified two subsites for D-Ala binding in the active site (11,12). Structural (13)(14)(15)(16)(17)(18) and mutagenesis (19) studies have shown that many of the residues involved in substrate binding and catalysis are conserved in the D-Ala:D-X ligase superfamily.…”

mentioning

confidence: 99%

Structural and Functional Characterization of VanG d-Ala:d-Ser Ligase Associated with Vancomycin Resistance in Enterococcus faecalis

Meziane‐Cherif

Saul

Haouz

et al. 2012

Journal of Biological Chemistry

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“…The VRSA-9 and VRSA-6 Ddl dimeric structures could be superimposed with an overall root mean square (RMS) deviation of 1.2 Å in alpha carbon positions. As in VRSA-6 Ddl, each monomer was divided into three ␣/␤ domains: an N-terminal domain (1 to 120), a central domain (121 to 218), and a C-terminal domain (219 to 356) (19). The mutated residues A283E and Q260K in VRSA-9 Ddl were located in the C-terminal domain, A283E at the dimer interface and Q260K in an exposed external loop (Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular Basis of Vancomycin Dependence in VanA-Type Staphylococcus aureus VRSA-9

Meziane‐Cherif

Saul²,

Moubareck

et al. 2010

J Bacteriol

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The vancomycin-resistant Staphylococcus aureus VRSA-9 clinical isolate was partially dependent on glycopeptide for growth. The responsible vanA operon had the same organization as that of Tn1546 and was located on a plasmid. The chromosomal D-Ala:D-Ala ligase (ddl) gene had two point mutations that led to Q260K and A283E substitutions, resulting in a 200-fold decrease in enzymatic activity compared to that of the wild-type strain VRSA-6. To gain insight into the mechanism of enzyme impairment, we determined the crystal structure of VRSA-9 Ddl and showed that the A283E mutation induces new ion pair/hydrogen bond interactions, leading to an asymmetric rearrangement of side chains in the dimer interface. The Q260K substitution is located in an exposed external loop and did not induce any significant conformational change. The VRSA-9 strain was susceptible to oxacillin due to synthesis of pentadepsipeptide precursors ending in D-alanyl-D-lactate which are not substrates for the ␤-lactam-resistant penicillin binding protein PBP2. Comparison with the partially vancomycin-dependent VRSA-7, whose Ddl is 5-fold less efficient than that of VRSA-9, indicated that the levels of vancomycin dependence and susceptibility to ␤-lactams correlate with the degree of Ddl impairment. Ddl drug targeting could therefore be an effective strategy against vancomycin-resistant S. aureus. Methicillin-resistant

show abstract

Allosteric inhibition of Staphylococcus aureus d -alanine: d -alanine ligase revealed by crystallographic studies

Abstract: antibiotic ͉ crystallography ͉ inhibition mechanism ͉ kinetics ͉ cell wall synthesis

Cited by 80 publications

References 27 publications

Treponema pallidumPutative Novel Drug Target Identification and Validation: Rethinking Syphilis Therapeutics with Plant-Derived Terpenoids

Treponema pallidumPutative Novel Drug Target Identification and Validation: Rethinking Syphilis Therapeutics with Plant-Derived Terpenoids

Structural and Functional Characterization of VanG d-Ala:d-Ser Ligase Associated with Vancomycin Resistance in Enterococcus faecalis

Molecular Basis of Vancomycin Dependence in VanA-Type Staphylococcus aureus VRSA-9

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