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L-leucine increases the sensitivity of drug-resistant Salmonella to sarafloxacin by stimulating central carbon metabolism and increasing intracellular reactive oxygen species level (LC-MS positive mode)

ABSTRACT:

The overuse of antibiotics has made public health and safety face a serious crisis. It is urgent to develop new clinical treatment methods to combat drug-resistant bacteria to alleviate the health crisis. The efficiency of antibiotics is closely related to the metabolic state of bacteria. However, studies on fluoroquinolone-resistant Salmonella are relatively rare. In this study, non-targeted metabolomics was used to analyze the metabolic difference between sarafloxacin-susceptible Salmonella Typhimurium (SAR-S) and sarafloxacin-resistant Salmonella Typhimurium (SAR-R), and found that the central carbon metabolism was weakened due to drug resistance. We also confirmed that exogenous L-leucine increased the killing effect of sarafloxacin on SAR-R and other clinically resistant Salmonella serotypes. Exogenous L-leucine stimulated the metabolic state of bacteria, especially the TCA cycle, which increased the working efficiency of the electron transfer chain and increased the intracellular NADH, ATP concentrationa nd reactive oxygen species level. Furthermore, we used real-time quantitative PCR to confirm the changes in various metabolic characteristics. Our results suggest that when the metabolism of drug-resistant bacteria is reprogrammed, the bactericidal effect of antibiotics improves. This study further enhances research in the anti-drug resistance field at the metabolic level and provides theoretical support for solving the current problem of sarafloxacin drug resistance, a unique fluoroquinolone drug for animals. To sum up, our research results showed that exogenous L-leucine promotes the bactericidal effect of antibiotics through metabolic modification of drug-resistant bacteria, which has the potential as a new adjuvant of antibiotics.

LC-MS positive mode is reported in the current study MTBLS7711.

LC-MS negative mode is reported in MTBLS7713.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic

SUBMITTER: Heng Yang

PROVIDER: MTBLS7711 | MetaboLights | 2023-05-02

REPOSITORIES: MetaboLights

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Project description:The overuse of antibiotics has made public health and safety face a serious crisis. It is urgent to develop new clinical treatment methods to combat drug-resistant bacteria to alleviate the health crisis. The efficiency of antibiotics is closely related to the metabolic state of bacteria. However, studies on fluoroquinolone-resistant Salmonella are relatively rare. In this study, non-targeted metabolomics was used to analyze the metabolic difference between sarafloxacin-susceptible Salmonella Typhimurium (SAR-S) and sarafloxacin-resistant Salmonella Typhimurium (SAR-R), and found that the central carbon metabolism was weakened due to drug resistance. We also confirmed that exogenous L-leucine increased the killing effect of sarafloxacin on SAR-R and other clinically resistant Salmonella serotypes. Exogenous L-leucine stimulated the metabolic state of bacteria, especially the TCA cycle, which increased the working efficiency of the electron transfer chain and increased the intracellular NADH, ATP concentration and reactive oxygen species level. Furthermore, we used real-time quantitative PCR to confirm the changes in various metabolic characteristics. Our results suggest that when the metabolism of drug-resistant bacteria is reprogrammed, the bactericidal effect of antibiotics improves. This study further enhances research in the anti-drug resistance field at the metabolic level and provides theoretical support for solving the current problem of sarafloxacin drug resistance, a unique fluoroquinolone drug for animals. To sum up, our research results showed that exogenous L-leucine promotes the bactericidal effect of antibiotics through metabolic modification of drug-resistant bacteria, which has the potential as a new adjuvant of antibiotics. LC-MS negative mode is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7713' rel='noopener noreferrer' target='_blank'>MTBLS7713</a>.LC-MS positive mode is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7711' rel='noopener noreferrer' target='_blank'>MTBLS7711</a>.

Project description:Kaiser2014 - Salmonella persistence after ciprofloxacin treatment The model describes the bacterial tolerance to antibiotics. Using a mouse model for Salmonella diarrhea, the authors have found that bacterial persistence occurs in the presence of the antibiotic ciprofloxacin because Salmonella can exist in two different states. One, the fast-growing population that spreads in the host's tissues and the other, slow-growing "persister" population that hide out inside dendritic cells of the host's immune system and cannot be attacked by the antibiotics. However, this can be killed by adding agents that directly stimulate the host's immune defense. This model is described in the article: Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment. Kaiser P, Regoes RR, Dolowschiak T, Wotzka SY, Lengefeld J, Slack E, Grant AJ, Ackermann M, Hardt WD. PLoS Biol. 2014 Feb 18;12(2):e1001793. Abstract: In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics. This model is hosted on BioModels Database and identified by: MODEL1312170001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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L-leucine increases the sensitivity of drug-resistant Salmonella to sarafloxacin by stimulating central carbon metabolism and increasing intracellular reactive oxygen species level (LC-MS positive mode)

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