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Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity.

Yamada Y, Takashima H, Walmsley DL, Ushiyama F, Matsuda Y, Kanazawa H, Yamaguchi-Sasaki T, Tanaka-Yamamoto N, Yamagishi J, Kurimoto-Tsuruta R, Ogata Y, Ohtake N, Angove H, Baker L, Harris R, Macias A, Robertson A, Surgenor A, Watanabe H, Nakano K, Mima M, Iwamoto K, Okada A, Takata I, Hitaka K, Tanaka A, Fujita K, Sugiyama H, Hubbard RE
J Med Chem 63 14805-14820 (2020)
Related entries: 7ci4, 7ci5, 7ci6, 7ci7, 7ci8, 7ci9, 7cia, 7cib, 7cic, 7cid

Cited: 11 times
EuropePMC logo PMID: 33210531

Abstract

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Reviews citing this publication (8)

  1. Fragment-to-Lead Medicinal Chemistry Publications in 2020. de Esch IJP, Erlanson DA, Jahnke W, Johnson CN, Walsh L. J Med Chem 65 84-99 (2022)
  2. Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria. Zhou P, Hong J. Acc Chem Res 54 1623-1634 (2021)
  3. Using Structure-guided Fragment-Based Drug Discovery to Target Pseudomonas aeruginosa Infections in Cystic Fibrosis. Arif SM, Floto RA, Blundell TL. Front Mol Biosci 9 857000 (2022)
  4. Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives. Di Leo R, Cuffaro D, Rossello A, Nuti E. Molecules 28 4378 (2023)
  5. Breaking down the cell wall: Still an attractive antibacterial strategy. Zhou J, Cai Y, Liu Y, An H, Deng K, Ashraf MA, Zou L, Wang J. Front Microbiol 13 952633 (2022)
  6. Fragment-Based Lead Discovery Strategies in Antimicrobial Drug Discovery. Konaklieva MI, Plotkin BJ. Antibiotics (Basel) 12 315 (2023)
  7. Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance. Romano KP, Hung DT. Biochim Biophys Acta Mol Cell Res 1870 119407 (2023)
  8. Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections. Theuretzbacher U, Blasco B, Duffey M, Piddock LJV. Nat Rev Drug Discov (2023)

Articles citing this publication (3)

  1. Identification of Therapeutic Targets in an Emerging Gastrointestinal Pathogen Campylobacter ureolyticus and Possible Intervention through Natural Products. Khan K, Basharat Z, Jalal K, Mashraqi MM, Alzamami A, Alshamrani S, Uddin R. Antibiotics (Basel) 11 680 (2022)
  2. Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens. Zhao J, Cochrane CS, Najeeb J, Gooden D, Sciandra C, Fan P, Lemaitre N, Newns K, Nicholas RA, Guan Z, Thaden JT, Fowler VG, Spasojevic I, Sebbane F, Toone EJ, Duncan C, Gammans R, Zhou P. Sci Transl Med 15 eadf5668 (2023)
  3. Machine learning approaches to study the structure-activity relationships of LpxC inhibitors. Yu T, Chong LC, Nantasenamat C, Anuwongcharoen N, Piacham T. EXCLI J 22 975-991 (2023)


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