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

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.

SUBMITTER: Hubner I

PROVIDER: S-EPMC8006170 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Soil bacteria can be prolific producers of secondary metabolites and other biologically active compounds of economic and clinical importance. These natural products are often synthesized by large multi-enzyme complexes such as polyketide synthases (PKSs) or non-ribosomal peptide synthases (NRPSs). The plant-associated Gram-negative bacterium, Serratia plymuthica A153, produces several secondary metabolites and is capable of killing the nematode worm Caenorhabditis elegans; a commonly used model for the study of bacterial virulence. In this study, we show that disruption of the hybrid PKS/NRPS zeamine (zmn) gene cluster results in the attenuation of "fast-killing" of C. elegans, indicating that zeamine has nematicidal activity. C. elegans also exhibits age-dependent susceptibility to zeamine, with younger worms being most sensitive to the bioactive molecule. The zmn gene cluster is widely distributed within Serratia and phytopathogenic Dickeya species and investigation of strains harboring the zmn gene cluster showed that several of them are highly virulent in C. elegans. Zeamine was described previously as a phytotoxin and broad-spectrum antibacterial compound. In addition to its nematicidal properties, we show here that zeamine can also kill Saccharomyces cerevisiae and Schizosaccharomyces pombe. The expression of the zmn gene cluster and regulation of zeamine production were also investigated. Transcription of the cluster was growth phase-dependent, and was modulated by the post-transcriptional RNA chaperone, Hfq. The results of this study show that zeamine is a highly toxic molecule with little, or no, apparent host specificity in very diverse biological systems. In its current form, zeamine(s) may be useful as a lead compound suitable for chemical modification and structure-activity assays. However, because of widespread non-selective toxicity in multiple bioassays, unmodified zeamine(s) is unlikely to be suitable as a therapeutic antibiotic.

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

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