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Broad Spectrum Antibiotic Xanthocillin X Effectively Kills Acinetobacter baumannii via Dysregulation of Heme Biosynthesis

Hübner, Ines
; 
Shapiro, Justin A.
; 
Hoßmann, Jörn
; 
Drechsel, Jonas
; 
Hacker, Stephan M.
; 
Rather, Philip N.
; 
Pieper, Dietmar H.
; 
Wuest, William M.
; 
Sieber, Stephan A.
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Issue Date
2021-01-20
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Abstract
Isonitrile natural products exhibit promising antibacterial activities. However, their mechanism of action (MoA) remains largely unknown. Based on the nanomolar potency of xanthocillin X (Xan) against diverse difficult-to-treat Gram-negative bacteria, including the critical priority pathogen Acinetobacter baumannii, we performed in-depth studies to decipher its MoA. While neither metal binding nor cellular protein targets were detected as relevant for Xan’s antibiotic effects, sequencing of resistant strains revealed a conserved mutation in the heme biosynthesis enzyme porphobilinogen synthase (PbgS). This mutation caused impaired enzymatic efficiency indicative of reduced heme production. This discovery led to the validation of an untapped mechanism, by which direct heme sequestration of Xan prevents its binding into cognate enzyme pockets resulting in uncontrolled cofactor biosynthesis, accumulation of porphyrins, and corresponding stress with deleterious effects for bacterial viability. Thus, Xan represents a promising antibiotic displaying activity even against multidrug resistant strains, while exhibiting low toxicity to human cells.
Citation
ACS Cent. Sci. 2374-7943 doi: 10.1021/acscentsci.0c01621.
Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Publisher
American Chemical Society (ACS)
Journal
ACS Central Science
URI
http://hdl.handle.net/10033/622765
DOI
10.1021/acscentsci.0c01621
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PubMed Central ID
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Article
Language
en
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ISSN
2374-7943
EISSN
2374-7951
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Gov't Doc #
Sponsors
U.S. Department of Veterans Affairs
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Attribution 4.0 International
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publications of the work group microbial interactions and processes (MINP)