Structure–activity relationships of novel potent MurF inhibitors

Gu, Yu; Florjancic, Alan S.; Clark, Richard F.; Zhang, Tianyuan; Cooper, Curt S.; Anderson, David D.; Lerner, Claude G.; McCall, Jennifer; Cai, Yingna; Black-Schaefer, Candace; Stamper, G.F.; Hajduk, Philip J.; Beutel, Bruce A.

doi:10.1016/j.bmcl.2003.09.073

Cited by 47 publications

(23 citation statements)

References 15 publications

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“…Phosphinate transition-state analogs of the MurC to -F enzymes were synthesized by various groups in the 1990s, and some of these showed potent enzyme inhibition (at low nanomolar levels for some, illustrating druggability of the targets) but no antibacterial activity, presumably due to a lack of cell entry (127,254,310,362,403). A number of inhibitors of MurB, -C, -D, and -F, found via screens for enzyme inhibition or binding, had micromolar (in some cases, low micromolar) 50% inhibitory concentrations (IC 50 s) and no (or weak in one case [370]) antibacterial activity (11,30,103,141,364,370).…”

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

“…Thus, these inhibitors can enter the cell (permeable E. coli) and exert an inhibitory effect on MurF, but the antibacterial effect was not shown to be due exclusively or at all to MurF inhibition. This is in contrast to The fact that the MurB to -F enzymes lack validation (as useful antibacterial targets) with inhibitors, even though they have been shown genetically to be essential, is curious and has been commented on in the literature (141,336,351,368). One speculative possibility, against which there is no clear evidence, is that the action of the pathway is concerted, perhaps performing as a multienzyme complex with channeling of intermediates, the active site(s) being inaccessible to inhibitors.…”

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

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Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,138

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,138

961

View full text Add to dashboard Cite

show abstract

“…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). The DDLA enzyme protein of the D-alanine metabolic pathway has also been used as a potential drug target in M. tuberculosis, S. aureus, Helicobacter pylori, and Escherichia coli (Bruning et al, 2010;Wu et al, 2008).…”

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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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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“…D-cycloserine and O-carbamyl-D-serine are known inhibitors for D-Ala-D-Ala pathways Alr and Ddl, [21][22][23] and recently a few synthetic compounds were reported as MurF inhibitors. 24 To date, there are some reports on the assay method for D-Ala-D-Ala pathway 25,26 and MurF, 27,28 but none of them are high-throughput functional assays appropriate for largescale natural product screenings. In this paper, we describe the development of a cell-free assay to measure the sequential reactions of D-Ala-D-Ala formation and MurF coupled with translocase I.…”

Section: Introductionmentioning

confidence: 99%

A novel assay of bacterial peptidoglycan synthesis for natural product screening

et al. 2009

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Although a large number of microbial metabolites have been discovered as inhibitors of bacterial peptidoglycan biosynthesis, only a few inhibitors were reported for the pathway of UDP-MurNAc-pentapeptide formation, partly because of the lack of assays appropriate for natural product screening. Among the pathway enzymes, D-Ala racemase (Alr), D-Ala:D-Ala ligase (Ddl) and UDPMurNAc-tripeptide:D-Ala-D-Ala transferase (MurF) are particularly attractive as antibacterial targets, because these enzymes are essential for growth and utilize low-molecular-weight substrates. Using dansylated UDP-MurNAc-tripeptide and L-Ala as the substrates, we established a cell-free assay to measure the sequential reactions of Alr, Ddl and MurF coupled with translocase I. This assay is sensitive and robust enough to screen mixtures of microbial metabolites, and enables us to distinguish the inhibitors for D-Ala-D-Ala formation, MurF and translocase I. D-cycloserine, the D-Ala-D-Ala pathway inhibitor, was successfully detected by this assay (IC 50 ¼1.7 lg ml À1 ). In a large-scale screening of natural products, we have identified inhibitors for D-Ala-D-Ala synthesis pathway, MurF and translocase I.

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Structure–activity relationships of novel potent MurF inhibitors

Cited by 47 publications

References 15 publications

Challenges of Antibacterial Discovery

Challenges of Antibacterial Discovery

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

A novel assay of bacterial peptidoglycan synthesis for natural product screening

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