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

Host stress drives tolerance and persistence: The bane of anti-microbial therapeutics DOI Creative Commons
Sophie Hélaine, Brian P. Conlon, Kimberly M. Davis

et al.

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(6), P. 852 - 862

Published: June 1, 2024

Antibiotic resistance, typically associated with genetic changes within a bacterial population, is frequent contributor to antibiotic treatment failures. persistence and tolerance, which we collectively term recalcitrance, represent transient phenotypic in the population that prolong survival presence of lethal concentrations antibiotics. recalcitrance challenging detect investigate-traditionally studied under vitro conditions, our understanding during infection its contribution failure limited. Recently, significant progress has been made study antibiotic-recalcitrant populations pathogenic species, including Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica, Yersiniae, context host environment. Despite diversity these pathogens models, shared signals responses promote common features vulnerabilities persisters tolerant bacteria have emerged. These will be discussed here, along toward developing therapeutic interventions better treat recalcitrant pathogens.

Language: Английский

Citations

16
Disruption of sulfur transferase complex increases bacterial intramacrophage persistence DOI Creative Commons

Huang Tang,

Zuoqiang Wang,

Congcong Li

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(5), P. e1013136 - e1013136

Published: May 14, 2025

Bacterial persisters contribute significantly to clinical treatment failure and relapse. These cells could resist antibiotic via transient phenotypic gene expression alterations. We conducted a high-throughput screening of Salmonella Typhimurium transposon mutants identify key genes for intramacrophage persistence. The results show that sulfur transferase complex encoded by yheM , yheL, yheN trmU yhhP are involved in bacterial persist macrophages downregulating the during exposure high concentrations antibiotics, even persistent infection mouse model. Mechanistically, deletion increases reactive nitrogen species (RNS) exponential phase, which inhibits respiration ATP generation. In contrast, absence promotes persister formation elevating (p)ppGpp levels stationary phase. Taken together, our data demonstrate bacteria use coordinate replication persistence adaptation various environmental stresses. findings reveal role provide promising target antibacterial therapy.

Language: Английский

Citations

0
Antibiotic-recalcitrant Salmonella during infection DOI
Rachel T. Giorgio, Sophie Hélaine

Nature Reviews Microbiology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Language: Английский

Citations

1
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

Citations

0