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TitleDevelopment of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 5085, Year 2024
Publish dateJun 14, 2024
AuthorsKazuki Yamamoto / Toyotaka Sato / Aili Hao / Kenta Asao / Rintaro Kaguchi / Shintaro Kusaka / Radhakrishnam Raju Ruddarraju / Daichi Kazamori / Kiki Seo / Satoshi Takahashi / Motohiro Horiuchi / Shin-Ichi Yokota / Seok-Yong Lee / Satoshi Ichikawa /
PubMed AbstractMraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant ...MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.
External linksNat Commun / PubMed:38877016 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 2.88 Å
Structure data

44293

9b70

EMDB-44293, PDB-9b70:
Cryo-EM structure of MraY in complex with analogue 2
Method: EM (single particle) / Resolution: 2.88 Å

44294

9b71

EMDB-44294, PDB-9b71:
Cryo-EM structure of MraY in complex with analogue 3
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

PDB-1ai1:
HIV-1 V3 LOOP MIMIC

ChemComp-HOH:
WATER

PDB-1ai2:
ISOCITRATE DEHYDROGENASE COMPLEXED WITH ISOCITRATE, NADP+, AND CALCIUM (FLASH-COOLED)

Source
  • aquifex aeolicus vf5 (bacteria)
  • lama glama (llama)
KeywordsTRANSFERASE / inhibitor / antibiotics

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