Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1261917 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33530091_1.fastq.gz | Fastqsanger.gz | |||
| SRR33530091_2.fastq.gz | Fastqsanger.gz | |||
| SRR33530092_1.fastq.gz | Fastqsanger.gz | |||
| SRR33530092_2.fastq.gz | Fastqsanger.gz | |||
| SRR33530093_1.fastq.gz | Fastqsanger.gz |
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Project description:Overuse of cationic biocides including quaternary ammonium compounds (QACs) poses a growing threat by selecting for antimicrobial resistance. Here, we use Streptococcus gordonii, a commensal opportunistic pathogen, as a model to elucidate the mechanisms of QAC lethality and resistance. We show that QACs trigger V-type ATPase–driven metabolic dysfunction, leading to oxidative phosphorylation (OXPHOS) dominance and excessive reactive oxygen species (ROS) accumulation. Resistance arises through synergistic regulation by ClpX and PstB, which repress the competence pathway regulator ComDE and reprogram metabolism toward aerobic glycolysis, thereby limiting ROS production. Mechanistically, ClpX modulates ComDE signaling through protein aggregation and HtrA-mediated degradation of competence-stimulating peptide, while PstB governs ComDE via phosphorylation of the mannose-specific phosphotransferase system. Activation of ComDE restores ROS-mediated QAC lethality, identifying this pathway as a potential therapeutic target. These findings reveal that metabolic adaptation driven by competence regulon governs biocide susceptibility and adaptation, offering new strategies to counteract QAC resistance and associated cross-resistance in commensal bacteria.
2025-05-14 | PXD063944 |
Project description:Antibiotic resistance is a growing concern, yet resistance and cross-resistance to widely used chemical biocides are poorly understood. Here, we show that cationic biocides induce V-type ATPase overactivation in Streptococcus gordonii, shifting metabolism to oxidative phosphorylation and increasing ROS. This triggers protein aggregation (PAs), which amplifies ROS in a lethal feedback loop. Synergistic inactivation of ClpX, a protease ATPase subunit, and PstB, a phosphate transporter component, disrupts the PAs-ROS loop by suppressing the competence regulator ComDE and rewiring metabolism to glycolysis. ClpX inactivation alleviates proteotoxic stress, promoting HtrA-mediated CSP degradation and ComDE downregulation, while PstB dysfunction impairs mannose PTS phosphorylation to further suppress ComDE. Reactivation of ComDE restores biocide susceptibility through the PAs-ROS loop. This mechanism is conserved in other ComDE-encoding streptococci, including Streptococcus pneumoniae, underscoring ComDE-mediated metabolic adaptation as a key regulator of bacterial susceptibility to membrane-targeted and ROS-inducing antimicrobials, and suggesting strategies to mitigate resistance to chemical biocides.
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Project description:Adaptation of Listeria monocytogenes EGD-e to quaternary ammonium compounds
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Project description:Intratracheal instillation of quaternary ammonium compounds in rats
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Project description:The AAA+ ATPase ClpX recognizes diverse substrates and plays a crucial role in cellular homeostasis. Mycobacterium tuberculosis (Mtb) ClpX binds to two structurally distinct adaptors- the Single-stranded DNA binding protein (SSB) and the Small protein B (SmpB). The mechanistic features of adaptor-dependent modulation of ClpX activity and its functional implications still remain poorly understood. Results show that both adaptors bind to the N-terminal domain of ClpX, albeit with different stoichiometry. While SSB binding enhances ATPase activity, SmpB does not. Structural and biochemical experiments revealed that both adaptors substantially reduce conformational sampling and drive ClpX into a more compact, homogenous quaternary arrangement. The interactome of the adaptors and ClpX indicate features that distinguish adaptor-dependent from adaptor-independent ClpX activity. Changes in the expression profile in Mtb cells upon over-expression of either SSB or SmpB suggest functional linkages between the protein recycling mechanism and transcription. Mtb ClpX is thus both- an unfoldase driving protein maturation and a checkpoint regulator synchronizing transcription and translational processes in this slow-growing human pathogen.
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Project description:Streptococcus gordonii is a primary colonizer of the multispecies biofilm on tooth surfaces forming dental plaque, and a potential agent of endocarditis. The recent completion of the genome sequence of the naturally competent strain Challis allowed the design of a spotted oligonucleotide microarray to examine a genome-wide response of this organism to environmental signals. Based on temporal responses to synthetic competence signaling peptide (CSP) as indicated by transformation frequencies, the S. gordonii transcriptome was monitored at increments after CSP exposure. Microarray analysis identified 35 candidate early genes and 127 candidate late genes that were up-regulated at 5 and 15 minutes, respectively; these genes were often grouped in clusters. Findings supported published literature on the S. gordonii competence response, with up-regulation of most, but not all, genes that have been reported to affect this species' transformation frequencies. The CSP-induced transcriptomes of S. gordonii were compared to those of published S. pneumoniae strains. Both conserved and species-specific genes were identified. Putative intergenic regulatory sites such as the conserved combox sequence thought to be a binding site for competence sigma factor, were found preceding S. gordonii late responsive genes. In contrast, S. gordonii early CSP-responsive genes were not preceded by S. pneumoniae conserved direct repeats. These studies provide the first insights into a genome-wide transcriptional response of an oral commensal organism. They offer an extensive analysis of transcriptional changes that accompany competence in S. gordonii and form a basis for future intra- and inter-species comparative analyses of this ecologically important phenotype. Keywords: gene expression design
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