9C4M

Crystal Structure of A. baumannii GuaB dCBS with inhibitor G6 (3826)

This is a non-PDB format compatible entry.

Summary for 9C4M

• Entry DOI: 10.2210/pdb9c4m/pdb
• Descriptor: Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, N-[4-chloro-3-(morpholin-4-yl)phenyl]-N~2~-[3-(hydroxymethyl)quinolin-6-yl]-L-alaninamide, ... (4 entities in total)
• Functional Keywords: guab, impdh, antibiotic, oxidoreductase
• Biological source: Acinetobacter baumannii; More
• Total number of polymer chains: 8
• Total formula weight: 338492.06

Authors

Harris, S.F.,Wu, P. (deposition date: 2024-06-04, release date: 2024-09-18, Last modification date: 2024-11-06)

Primary citation

Peng, Y.,Moffat, J.G.,DuPai, C.,Kofoed, E.M.,Skippington, E.,Modrusan, Z.,Gloor, S.L.,Clark, K.,Xu, Y.,Li, S.,Chen, L.,Liu, X.,Wu, P.,Harris, S.F.,Wang, S.,Crawford, T.D.,Li, C.S.,Liu, Z.,Wai, J.,Tan, M.-.W.
Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli.
J.Bacteriol., 206:e0010224-e0010224, 2024

PubMed Abstract: Inosine 5'-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: and . Specifically, the GuaB inhibitor G6 rapidly kills but only kills after 24 h. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.IMPORTANCE is a priority bacterial pathogen for which development of new antibiotics is urgently needed due to the emergence of multidrug resistance. We recently developed a series of specific inhibitors against GuaB, a bacterial inosine 5'-monophosphate dehydrogenase, and achieved sub-micromolar minimum inhibitory concentrations against . GuaB catalyzes the rate-limiting step of guanine biosynthesis and is highly conserved across bacterial pathogens. This study shows that inhibition of GuaB induced a bacterial morphological profile distinct from that of other classes of antibiotics, highlighting a novel mechanism of action. Moreover, our transcriptomic analysis showed that regulation of purine biosynthesis and stress responses of upon GuaB inhibition differed significantly from that of .

PubMed: 39235234
DOI: 10.1128/jb.00102-24

Experimental method

X-RAY DIFFRACTION (2.48 Å)