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SpsB is a target of SOS-response inhibitor OXF‑077 and regulates quinolone resistance emergence

ABSTRACT: Antimicrobial resistance (AMR) is a global health threat, urgently requiring novel compounds with new targets. One emerging strategy is the development of ‘antibiotic adjuvants’ that inhibit the mutagenic SOS response in bacteria, thus prolonging antibiotic efficacy. OXF‑077 is a potent SOS-response inhibitor that suppresses the emergence of ciprofloxacin resistance in Staphylococcus aureus; however, the cellular target of OXF-077 is unknown. We report here the use of affinity-based protein profiling to identify signal peptidase IB (SpsB) as a target of OXF‑077. Genetic and chemical studies demonstrated that SpsB is required for upregulation of the SOS response gene recA and increased frequency of resistance to ciprofloxacin. SpsB is therefore postulated to regulate the SOS response in S. aureus, representing a cell surface peptidase that can be targeted by small-molecules to slow the evolution of resistance. Collectively, this work delivers SpsB as an attractive target to combat the urgent threat of AMR.

INSTRUMENT(S):

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Vaishnavi Ravikumar

LAB HEAD: Thomas Lanyon-Hogg

PROVIDER: PXD071059 | Pride | 2026-05-21

REPOSITORIES: Pride

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			Action	DRS
	JB_250603_0.01FDR_60min_gradient.xlsx	Xlsx
	QEX02_MF_250528_JB-J2-rerun_142.raw	Raw
	QEX02_MF_250528_JB-J3-rerun_144.raw	Raw
	QEX02_VR_250605_JB_010_rerun_047.raw	Raw
	QEX02_VR_250605_JB_020_rerun_049.raw	Raw

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Project description:Background: Antibiotic resistance is an urgent threat to public health. Prior to the evolution of antibiotic resistance, bacteria frequently undergo response and tend to develop a state of adaption to the antibiotic. Ciprofloxacin is a broad-spectrum antibiotic by damaging DNA. With the widespread clinical application, the resistance of bacteria to ciprofloxacin continues to increase. This study aimed to investigate the transcriptome changes under the action of high concentration of ciprofloxacin in Escherichia coli. Results: We identified 773 up-regulated differentially expressed genes (DEGs) and 645 down-regulated DEGs in ciprofloxacin treated cells. Enriched biological pathways reflected the up-regulation of biological process such as DNA damage and repair system, toxin/antitoxin systems, formaldehyde detoxification system, peptide biosynthetic process and cellular protein metabolic process. With KEGG pathway analysis, up-regulated DEGs of kdsA and waa operon were associated with “LPS biosynthesis”. rfbABC operon was related to “streptomycin biosynthesis” and “polyketide sugar unit biosynthesis ”. Down-regulated DEGs of thrABC and fliL operons were associated with “flagellum-dependent cell motility” and “bacterial-type flagellum” in GO terms, and enriched into “biosynthesis of amino acids” and “flagellar assembly” in KEGG pathways. After treatment of ciprofloxacin, bacterial lipopolysacchride (LPS) release was increased by two times, and the mRNA expression level of LPS synthesis genes, waaB, waaP and waaG were elevated (P < 0.05). Conclusions: Characterization of the gene clusters by RNA-seq showed high dose of ciprofloxacin not only lead to damage of bacterial macromolecules and components, but also induce protective response against antibiotic action by up-regulating the SOS system, toxin/antitoxin system and formaldehyde detoxification system. Moreover, genes related to biosynthesis of LPS were also upregulated by the treatment indicating that ciprofloxacin can enhance the production of endotoxin on the level of transcription. These results demonstrated that transient exposure of high dose ciprofloxacin is double edged. Cautions should be taken when administering the high dose antibiotic treatment for infectious diseases.

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SpsB is a target of SOS-response inhibitor OXF‑077 and regulates quinolone resistance emergence

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