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Integrated Transcriptomic and Metabolomic Analyses Reveal the Antibacterial Mechanism of Isocorydine against Mycobacterium bovis

ABSTRACT:

Mycobacterium bovis, the causative agent of bovine tuberculosis, poses a significant zoonotic threat. This study defines the antibacterial activity and mechanism of the natural alkaloid isocorydine (ICD) against M. bovis using an integrated multi-omics approach. Phenotypic analyses demonstrated that ICD (MIC=400 μg/mL) disrupts cell wall and membrane integrity, causing ion leakage, extracellular pH alteration, lipid depletion, and severe ultrastructural damage. Transcriptomic profiling under sub-inhibitory ICD stress revealed 66 differentially expressed genes, with significant upregulation of efflux pumps (ABC transporters, MMPL, SMR) and their associated TetR family transcriptional regulators, indicating a targeted bacterial counter-response. Concurrently, metabolomic analysis identified 1,158 differential metabolites, depicting a state of profound metabolic dysregulation characterized by the depletion of central carbon metabolites (e.g., sugars, succinate) and the accumulation of fatty acids and precursors (e.g., oleic acid). Integrated pathway analysis highlighted critical disruptions in starch/sucrose metabolism, ABC transporters, and fatty acid biosynthesis. Our findings establish that ICD exerts its bactericidal effect primarily by targeting the cell envelope, causing irreparable physical damage and triggering a catastrophic metabolic crisis that overwhelms the bacterium's compensatory mechanisms. This work elucidates a multi-targeted antibacterial mechanism and positions ICD as a promising phytochemical lead for combating mycobacterial infections.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13441 | MetaboLights | 2025-12-03

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13441_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13441_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13441_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13441_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:The identification of multidrug resistant (MDR), extensively and totally drug resistant Mycobacterium tuberculosis (Mtb), in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS) compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS) at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S) microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB), cell wall biosynthesis (emb genes), protein synthesis (rpl) and additional central metabolic pathways (ppdK, pknH, pfkB) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB) in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-134]

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Integrated Transcriptomic and Metabolomic Analyses Reveal the Antibacterial Mechanism of Isocorydine against Mycobacterium bovis

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