Local Regulator AcrR Regulates Persister Formation by Repression of AcrAB Efflux Pump during Exponential Growth in Aeromonas veronii DOI
Xiang Ma,

Kang Hu,

Yuesheng Xiong

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 28, 2023

Bacterial persisters refer to a small fraction of dormant variants that survive treatment with high concentrations antibiotics. Increasing research indicates multidrug efflux pumps play major role in persister formation many Gram-negative organisms. In the present study, roles repressor AcrAB pump, AcrR, regulation activity and function efflux, as well production persisters, were investigated pathogen Aeromonas veronii, which causes huge economic losses aquatic industry threatens human health. We observed exclusively exponential-phase cells, not stationary-phase deletion acrR gene significantly (P < 0.05) promoted expression acrA acrB genes reduced intracellular accumulation substrate Hoechst 33342. Moreover, overexpression triggered decreased transcription promoter acrAB operon. The assay indicated loss pump under challenge all tested antibiotic types chloramphenicol, fluoroquinolone, tetracycline, β-lactam, while caused an exponential-phase-specific increase against β-lactam. Our results provide molecular insights into mechanism bacterial persistence by demonstrating for first time local regulator AcrR is involved modulation A. veronii through its repressive on during exponential growth period.

Language: Английский

The role of bacterial metabolism in antimicrobial resistance DOI
Mehrose Ahmad, Sai Varun Aduru, Robert P. Smith

et al.

Nature Reviews Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Language: Английский

Citations

6
Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance DOI Creative Commons
Amir Arastehfar, Farnaz Daneshnia,

Nathaly Cabrera

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 2, 2023

Abstract Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive proliferate within macrophages. Resembling bacterial persisters, subset genetically drug-susceptible C. cells can lethal exposure the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in , expanding persister reservoir from which echinocandin-resistant mutants emerge. We this associated with non-proliferation triggered by macrophage-induced oxidative stress, deletion genes involved reactive oxygen species detoxification significantly increases mutants. Finally, amphotericin B kill intracellular reducing resistance. Our study supports hypothesis intra-macrophage recalcitrant/drug-resistant alternating strategies be developed eliminate reservoir.

Language: Английский

Citations

30
Uracil restores susceptibility of methicillin-resistant Staphylococcus aureus to aminoglycosides through metabolic reprogramming DOI Creative Commons

Lvyuan Fan,

Zhiyu Pan,

Xu Liao

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 24, 2023

Background: Methicillin-resistant Staphylococcus aureus (MRSA) has now become a major nosocomial pathogen bacteria and resistant to many antibiotics. Therefore, Development of novel approaches combat the disease is especially important. The present study aimed provide approach involving use nucleotide-mediated metabolic reprogramming tackle intractable methicillin-resistant S. infections. Objective: This aims explore bacterial effects mechanism uracil gentamicin in aureus. Methods: Antibiotic bactericidal assays was used determine synergistic effect gentamicin. How did regulate metabolism including tricarboxylic acid (TCA) cycle by GC-MS-based metabolomics. Next, genes activity key enzymes TCA cycle, PMF, intracellular aminoglycosides were measured. Finally, respiration, reactive oxygen species (ROS), ATP levels also assayed this study. Results: In study, we found that could synergize with kill MRSA (USA300) 400-fold. Reprogramming metabolomics displayed reprogrammed metabolism, enhanced elevate NADH production proton motive force, thereby promoting uptake Furthermore, increased cellular respiration production, resulting generation ROS. Thus, combined antibiotics induced death. Inhibition or ROS attenuate efficiency. Moreover, exhibited cooperation against other pathogenic bacteria. mouse mode infection, combination survival rate infected mice. Conclusion: Our results suggest enhances Gram-positive modulating metabolism.

Language: Английский

Citations

26
Discovery of antibiotics that selectively kill metabolically dormant bacteria DOI

Erica J. Zheng,

Jacqueline A. Valeri,

Ian W. Andrews

et al.

Cell chemical biology, Journal Year: 2023, Volume and Issue: 31(4), P. 712 - 728.e9

Published: Nov. 28, 2023

Language: Английский

Citations

24
Laboratory Evolution of Antimicrobial Resistance in Bacteria to Develop Rational Treatment Strategies DOI Creative Commons
Tomoya Maeda, Chikara Furusawa

Antibiotics, Journal Year: 2024, Volume and Issue: 13(1), P. 94 - 94

Published: Jan. 18, 2024

Laboratory evolution studies, particularly with Escherichia coli, have yielded invaluable insights into the mechanisms of antimicrobial resistance (AMR). Recent investigations illuminated that, repetitive antibiotic exposures, bacterial populations will adapt and eventually become tolerant resistant to drugs. Through intensive analyses, these inquiries unveiled instances convergent across diverse antibiotics, pleiotropic effects mutations, role played by loss-of-function mutations in evolutionary landscape. Moreover, a quantitative analysis multidrug combinations has shed light on collateral sensitivity, revealing specific drug capable suppressing acquisition resistance. This review article introduces methodologies employed laboratory AMR bacteria presents recent discoveries concerning derived from evolution. Additionally, outlines application endeavors formulate rational treatment strategies.

Language: Английский

Citations

13
Biofilm antimicrobial susceptibility through an experimental evolutionary lens DOI Creative Commons
Tom Coenye, Mona Bové, Thomas Bjarnsholt

et al.

npj Biofilms and Microbiomes, Journal Year: 2022, Volume and Issue: 8(1)

Published: Oct. 18, 2022

Abstract Experimental evolution experiments in which bacterial populations are repeatedly exposed to an antimicrobial treatment, and examination of the genotype phenotype resulting evolved bacteria, can help shed light on mechanisms behind reduced susceptibility. In this review we present overview why it is important include biofilms experimental evolution, approaches available study what has taught us about tolerance resistance biofilms. Finally, emerging consensus view biofilm susceptibility supported by data obtained during studies.

Language: Английский

Citations

35
Citric Acid Confers Broad Antibiotic Tolerance through Alteration of Bacterial Metabolism and Oxidative Stress DOI Open Access
Xuesong Li,

Junze Xue,

Yu Qi

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 9089 - 9089

Published: May 22, 2023

Antibiotic tolerance has become an increasingly serious crisis that seriously threatened global public health. However, little is known about the exogenous factors can trigger development of antibiotic tolerance, both in vivo and vitro. Herein, we found addition citric acid, which used many fields, obviously weakened bactericidal activity antibiotics against various bacterial pathogens. This mechanistic study shows acid activated glyoxylate cycle by inhibiting ATP production bacteria, reduced cell respiration levels, inhibited tricarboxylic (TCA cycle). In addition, oxidative stress ability led to imbalance oxidation–antioxidant system. These effects together induced bacteria produce tolerance. Surprisingly, succinic xanthine could reverse vitro animal infection models. conclusion, these findings provide new insights into potential risks usage relationship between metabolism.

Language: Английский

Citations

19
Antibiotic tolerance: targeting bacterial survival DOI Creative Commons
Lucas Boeck

Current Opinion in Microbiology, Journal Year: 2023, Volume and Issue: 74, P. 102328 - 102328

Published: May 26, 2023

Antimicrobial susceptibility testing is the cornerstone of antibiotic treatments. Yet, active drugs are frequently unsuccessful in vivo and most clinical trials investigating antibiotics fail. So far, bacterial survival strategies, other than drug resistance, have been largely ignored. As such, tolerance persisters, allowing populations to survive during treatments, could fill a gap testing. Therefore, it remains critical establish robust scalable viability measures define relevance survivors across various infections. If successful, these tools improve design development prevent formation or target survivors, ultimately reduce treatment failures curb resistance evolution.

Language: Английский

Citations

18
A synthetic differentiation circuit in Escherichia coli for suppressing mutant takeover DOI Creative Commons
David S. Glass,

Anat Bren,

Elizabeth Vaisbourd

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(4), P. 931 - 944.e12

Published: Feb. 1, 2024

Differentiation is crucial for multicellularity. However, it inherently susceptible to mutant cells that fail differentiate. These mutants outcompete normal by excessive self-renewal. It remains unclear what mechanisms can resist such expansion. Here, we demonstrate a solution engineering synthetic differentiation circuit in Escherichia coli selects against these via biphasic fitness strategy. The provides tunable production of analogs stem, progenitor, and differentiated cells. resists mutations coupling the an essential enzyme, thereby disadvantaging non-differentiating mutants. selected maintained positive rate long-term evolution. Surprisingly, this remained constant across vast changes growth conditions. We found transit-amplifying (fast-growing progenitors) underlie environmental robustness. Our results provide insight into stability powerful method evolutionarily stable multicellular consortia.

Language: Английский

Citations

9
Citric acid plays a dual ‘synergistic/antagonistic’ role with antibiotics in multidrug-resistant Salmonella Typhimurium DOI Creative Commons

Bismi Phasaludeen,

Dania Mustafa Darwich,

Greeshma Bharathan

et al.

Food Bioscience, Journal Year: 2025, Volume and Issue: unknown, P. 105843 - 105843

Published: Jan. 1, 2025

Language: Английский

Citations

1