A host-directed adjuvant resuscitates and sensitizes intracellular bacterial persisters to antibiotics DOI
Kuan‐Yi Lu,

Xiangbo Yang,

Matthew J. G. Eldridge

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 30, 2024

Abstract There are two major problems in the field of antimicrobial chemotherapy–antibiotic resistance and antibiotic tolerance. In case tolerance, antibiotics fail to kill bacteria as their phenotypic state affords them protection from bactericidal activity antibiotic. Antibiotic tolerance can affect an entire bacterial population, or a subset cells known persister cells. Interaction with host induces formation numerous pathogens, reactive oxygen nitrogen species production being heavily implicated collapse energy levels entrance into tolerant state. Here, we developed high-throughput screen identify modulators for intracellular Staphylococcus aureus . The identified compound, KL1 , increases sensitizes population antibiotics, without causing cytotoxicity outgrowth. We demonstrate that exhibits adjuvant murine model S. bacteremia infection Salmonella Typhimurium Transcriptomic analysis further studies on its mechanism action reveal modulates immune response genes suppresses macrophages, alleviating one stressors induce Our findings highlight potential target by stimulating metabolism encourage larger efforts address at host–pathogen interface, particularly within milieu.

Language: Английский

How macrophage heterogeneity affects tuberculosis disease and therapy DOI
David G. Russell, Nelson V. Simwela,

Joshua T. Mattila

et al.

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

Citations

5
Drug tolerance and persistence in bacteria, fungi and cancer cells: Role of non-genetic heterogeneity DOI Creative Commons
Imane El Meouche, Paras Jain, Mohit Kumar Jolly

et al.

Translational Oncology, Journal Year: 2024, Volume and Issue: 49, P. 102069 - 102069

Published: Aug. 8, 2024

Language: Английский

Citations

5
Cross-Talk Between Signal Transduction Systems and Metabolic Networks in Bacterial Antibiotics Resistance and Tolerance DOI
Shuji Gao, Baobao Liu, Shuo Yuan

et al.

International Journal of Antimicrobial Agents, Journal Year: 2025, Volume and Issue: unknown, P. 107479 - 107479

Published: Feb. 1, 2025

Language: Английский

Citations

0
Methicillin-Resistant Staphylococcus aureus T144: A Hypervirulent Model Strain for Infection Models DOI Creative Commons
Changsi Mao, Yuan Liu, Meirong Song

et al.

Antibiotics, Journal Year: 2025, Volume and Issue: 14(3), P. 270 - 270

Published: March 6, 2025

Background/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) presents a major public health challenge due to its multidrug resistance and high virulence. Developing representative model strains is crucial for systematically assessing pathogenesis antimicrobial therapies. Methods: The highly virulent MRSA strain T144, isolated from pigs, was characterized through whole-genome sequencing susceptibility testing. Infection models were successfully established in Galleria mellonella mice evaluate A mouse lung infection specifically developed assess bacterial load dynamics, immune responses, the efficacy of vancomycin treatment. Results: T144 demonstrated broad-spectrum antibiotic mortality rates both models. Whole-genome identified multiple virulence-associated genes, including hemolysins enterotoxins. concentration 7 × 108 CFUs optimized establishing model. In model, rapid proliferation within first 24 h, followed by slower growth rate. Significant changes markers observed, with elevated levels pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17a, TNF-α) decreased IL-10 levels. Vancomycin treatment significantly improved survival reduced load, confirming model’s utility studies. Conclusions: successful establishment provides robust platform investigating against strains. These findings highlight potential as valuable developing novel therapeutic strategies.

Language: Английский

Citations

0
B Cells as a Host of Persistent Salmonella Typhimurium DOI Creative Commons

Alonso D. Cruz‐Cruz,

Jocelyn C. Pérez‐Lara,

Diana Zuleika Velazquez

et al.

Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

ABSTRACT Salmonella enterica serovar Typhimurium ( S . Tm) can colonise different intracellular niches, either actively dividing or remaining dormant to persist. Bacterial persisters are phenotypic variants that temporarily enter a nonreplicative state. This allows them evade host cell defences and antibiotics, leading chronic infections. We previously reported during periods, remains within B cells in the bone marrow spleen. However, dynamics of replication formation antibiotic tolerance infected have not been studied. Here we show favourable reservoir for bacterial persistence. In vitro vivo experiments identified non‐replicating, persistent subsets splenic cells. These non‐replicative tolerant antibiotics (cefotaxime ciprofloxacin), while replicative bacteria remain susceptible. Infected mice demonstrated viable, spleen cells, maintaining tolerance. Although acid intravacuolar pH SPI‐2 regulators (SsrA/SsrB) necessary persistence SehA/B RelE/B toxin‐antitoxin system facilitates phenotype Overall, nonreplicating, antibiotic‐tolerant

Language: Английский

Citations

0
Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment DOI

Shujun Cui,

Danyang Chong,

Yixin Wang

et al.

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

Citations

0
Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation DOI
Zhou‐Li Cheng, Shuyuan Zhang, Z. Wang

et al.

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
A small regulatory RNA controls antibiotic adaptation in Staphylococcus aureus by modulating efflux pump expression DOI Creative Commons
Kam Pou Ha, Etornam Kofi Kumeko, Philippe Bouloc

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Staphylococcus aureus is an opportunistic pathogen that poses a considerable burden to healthcare settings worldwide, aided by its ability thrive in different environmental growth conditions and survive exposure antibiotics. Small regulatory RNAs (sRNAs) are decisive enhancing bacterial fitness modulating gene expression response changing conditions. We investigated the role of sRNAs adaptation S. By assessing library sRNA mutants, we identified RsaA required for optimal when exposed low concentrations fluoroquinolone, class antibiotics targeting DNA replication. also found absence RsaA, less susceptible β-lactam antibiotics, which act on cell wall. has been reported prevent MgrA, master protein controlling efflux pumps. Here, show affects sensitivity fluoroquinolone through MgrA. two forms, short one commonly referred studies, long form about twice length, known. Interestingly, our phenotype was only restored complemented with or it supplied parts, missing part obtain form. This work demonstrates antibiotic resistance highlights their value as potential therapeutic targets manipulating individual responses promote efficacy existing

Language: Английский

Citations

0
Increased Expression of AbcA Efflux Pump Accelerated Resistance Development from Tolerance to Resistance Against Oxacillin in Staphylococcus aureus DOI Creative Commons
Xiaohui Yu, Miaomiao Liu, Pilong Liu

et al.

Microorganisms, Journal Year: 2025, Volume and Issue: 13(5), P. 1140 - 1140

Published: May 16, 2025

Bacterial tolerance, especially in Staphylococcus aureus (S. aureus), may arise under intermittent antibiotic regimens and act as a stepping stone toward resistance development. However, the transition from tolerance to its contributing factors remain poorly understood. This study explores role of efflux pump gene abcA this process. mutants (overexpression, knockout, complementation) were constructed via homologous recombination. These strains subjected 21 cycles exposure oxacillin at 20× MIC, evolution was monitored. Spontaneous mutation frequencies survival abilities these also measured determine their involvement The overexpression mutant exhibited faster development compared wildtype strain. Conversely, knockout maintained susceptibility oxacillin, with no significant changes relative MIC. Increased frequency enhanced observed strain, whereas both reduced knockout. significantly accelerated S. by promoting spontaneous mutations bacterial survival. Disrupting offer novel strategy prevent resistance.

Language: Английский

Citations

0
Identification of the Cytotoxic Transglutaminase from Mycobacterium spp. That Is Involved in RIPK1 Activation DOI Creative Commons

Xinting Zhang,

Yikai Zhang, Xiao Feng

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(10), P. 2251 - 2251

Published: May 21, 2025

Although the global incidence of tuberculosis has declined in recent years, remains a major public health challenge. The Mycobacterium complex (MTBC) including M. tuberculosis, bovis, microti, etc., is deadliest spp. that needs more attention. Research on microti significant as it zoonotic pathogen can spread between animals and humans. By exploring function transglutaminase (MmTG), which widely distributed other species, potential cytotoxic effector been characterized. MmTG inhibits cell proliferation by inducing phosphorylation RIPK1 (receptor-interacting serine/threonine-protein kinase 1) Cys159 highly conserved residue related to its cytotoxicity. Understanding homologs provide insights into pathogenic mechanisms mycobacteria contribute development effective therapeutic strategies against mycobacterial infections.

Language: Английский

Citations

0