Bacterial persisters: molecular mechanisms and therapeutic development

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: July 17, 2024

Abstract Persisters refer to genetically drug susceptible quiescent (non-growing or slow growing) bacteria that survive in stress environments such as antibiotic exposure, acidic and starvation conditions. These cells can regrow after removal remain the same stress. are underlying problems of treating chronic persistent infections relapse treatment, resistance development, biofilm infections, pose significant challenges for effective treatments. Understanding characteristics exact mechanisms persister formation, especially key molecules affect formation survival persisters is critical more treatment infections. Currently, genes related being discovered confirmed, but by which form very complex, there still many unanswered questions. This article comprehensively summarizes historical background bacterial persisters, details their complex relationship with tolerant resistant bacteria, systematically elucidates interplay between various biological processes cells, well consolidates diverse anti-persister compounds We hope provide theoretical in-depth research on suggest new ideas choosing strategies

Language: Английский

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Zeolitic Imidazolate Framework‐8 Triggers the Inhibition of Arginine Biosynthesis to Combat Methicillin‐Resistant Staphylococcus Aureus

Small, Journal Year: 2023, Volume and Issue: 19(14)

Published: Jan. 5, 2023

The self-preservation and intelligent survival abilities of methicillin-resistant Staphylococcus aureus (MRSA) result in the ineffective treatment many antibiotics. Nano-drug delivery systems have emerged as a new strategy to overcome MRSA infection. ZIF-8 nanoparticles (ZIF-8 NPs) exhibit good antibacterial activities, while its molecular mechanisms are largely elusive. In this study, NPs prepared using room temperature solution reaction method. values minimum inhibitory concentration against Escherichia coli isolates 25 12.5 µg mL-1 , respectively. Transcriptome metabonomic analyses reveal that could trigger inhibition arginine biosynthesis pathway production ROS, which lead dysfunctional tricarboxylic acid cycle disruption cell membrane integrity, eventually killing isolates. Moreover, show desirable repair effects on mice model wound infected-model. results, for first time, mediates ROS energy metabolism dysfunction contributes ability MRSA. This study offers insight into combating

Language: Английский

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The RNA-Binding Protein ProQ Promotes Antibiotic Persistence in Salmonella

mBio, Journal Year: 2022, Volume and Issue: 13(6)

Published: Nov. 21, 2022

Bacterial populations can survive exposure to antibiotics through transient phenotypic and gene expression changes. These changes be attributed a small subpopulation of bacteria, giving rise antibiotic persistence. Although this phenomenon has been known for decades, much remains learned about the mechanisms that drive persister formation. The RNA-binding protein ProQ recently emerged as global regulator expression. Here, we show impacts formation in Salmonella. In vitro, contributes growth arrest subset cells are able treatment at high concentrations different antibiotics. underlying mechanism ProQ-dependent involves activation metabolically costly processes, including flagellar pathway type III secretion system encoded on Salmonella pathogenicity island 2. Importantly, phenotype is relevant during macrophage infection allows combined action host immune defenses Together, our data highlight importance persistence pathogenesis. IMPORTANCE Bacteria avoid eradication by Persister arise heterogeneity constitute fraction dormant within population actively growing which susceptible killing. study, ProQ, an expression, promotes persisters human pathogen enterica serovar Typhimurium. lacking proQ outcompete wild-type bacteria under laboratory conditions, less prone enter dormancy, form fewer cells. basis these phenotypes lies ProQ's ability activate energy-consuming cellular motility secretion. macrophages, indicating important role

Language: Английский

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The (p)ppGpp synthetase Rsh promotes rifampicin tolerant persister cell formation in Brucella abortus by regulating the type II toxin-antitoxin module mbcTA

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: May 22, 2024

Persister cells are transiently tolerant to antibiotics and associated with recalcitrant chronic infections due recolonization of host after antibiotic removal. Brucella spp. facultative pathogens that establish intracellular infection cycles in which results persistent infections. abortus forms multi-drug persister promoted by the (p)ppGpp synthetase Rsh during rifampicin exposure. Here, we confirmed formation B. stationary phase treated enrofloxacin. Deletion gene for decreased level presence these drugs different growth phases. However, deletion strain varied phases other antibiotics. also was involved treatment under certain stress conditions, including acidic exposure PBS, heat stress. Moreover, impacted cell levels or enrofloxacin RAW264.7 macrophages. Certain typeIItoxin-antitoxin modules were upregulated various conditions . We established positively regulated type II toxin-antitoxin mbcTA rifampicin-tolerant elevated ATP when promoter overexpressed background phase. Our plays a key role persistence may serve as potent novel target combination development new therapeutic approaches prevention strategies treat

Language: Английский

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High-Throughput Screening of a Promoter Library Reveals New Persister Mechanisms in Escherichia Coli

Microbiology Spectrum, Journal Year: 2022, Volume and Issue: 10(1)

Published: Feb. 23, 2022

Persister cells are a small subpopulation of phenotypic variants that survive high concentrations bactericidal antibiotics. Their survival mechanisms not heritable and can be formed stochastically or triggered by environmental stresses such as antibiotic treatment. In this study, high-throughput screening an Escherichia coli promoter library subsequent validation experiments identified several genes whose expression was upregulated Among the genes, waaG, guaA, guaB were found to important in persister cell formation E. their deletion significantly enhanced sensitivity various The GuaA GuaB enzymes form upstream reactions ppGpp (a global molecule) biosynthesis, guaA drastically perturbs regulon coli. WaaG, lipopolysaccharide glucosyltransferase, plays role shaping outer membrane structure, waaG dissipates proton gradient (ΔpH) component cellular motive force (PMF), ATP production, reduces type I stationary phase. Active respiration phase, which drives PMF, previously shown play critical formation, our results associated with deficient strain further corroborate these findings. IMPORTANCE Persistence is nonheritable trait normal growing switch phenotypically tolerant cells. This transient state enables recover grow into antibiotic-sensitive population. have been observed many pathogenic nonpathogenic bacteria. Previous studies highlight complexity diversity bacterial persister-cell mechanisms, still remain elucidated. Here, using knockout libraries coli, we reveal novel mechanisms. As persistence strategy evolved bacteria, study will enhance current molecular-level understanding conserved mechanism.

Language: Английский

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CRP and IHF act as host regulators in Royal Jelly's antibacterial activity

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 21, 2024

Royal Jelly (RJ) is a natural substance produced by honeybees, serving not only as nutrition for bee brood and queens but also functional food due to its health-promoting properties. Despite well-known broad-spectrum antibacterial activity, the precise molecular mechanism underlying action has remained elusive. In this study, we investigated impact of RJ on bacteria model MG1655 at half-maximal inhibitory concentration, employing LC-MS/MS analyze proteomic changes. The differentially expressed proteins were found primarily contribute suppression gene expression processes, specifically transcription translation, disrupting energy metabolism, inducing oxidative stress. Notably, treatment led marked inhibition superoxide dismutase catalase activities, resulting in heightened damage lipid peroxidation. Furthermore, through protein-protein interaction network analysis using STRING database, identified CRP IHF crucial host regulators responsive RJ. These play pivotal role suppressing essential hub genes associated with production antioxidant capabilities. Our findings significantly understanding RJ's mechanism, highlighting potential alternative conventional antibiotics. identification central players highlights intricate regulatory networks involved action, offering new targets developing innovative antimicrobial strategies.

Language: Английский

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Disruption of sulfur transferase complex increases bacterial intramacrophage persistence

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

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The Intersection between Bacterial Metabolism and Innate Immunity

Journal of Innate Immunity, Journal Year: 2023, Volume and Issue: 15(1), P. 782 - 803

Published: Jan. 1, 2023

<b><i>Background:</i></b> The innate immune system is the first line of defense against microbial pathogens and essential for maintaining good health. If breach barriers, likelihood infection significantly increased. Many bacterial pose a threat to human health on account their ability evade immunity survive in growth-restricted environments. These have evolved sophisticated strategies obtain nutrients as well manipulate responses, resulting disease or chronic infection. <b><i>Summary:</i></b> relationship between metabolism complex. Although aspects can be beneficial host, particularly those related microbiota barrier integrity, others harmful. Several harness responses persist during study these adaptive traits provides insight into roles pathogenesis that extend beyond energy balance. This review considers recent studies metabolic pathways promote by circumventing several facets system. We also discuss relationships antibiotics highlight future directions research this field. <b><i>Key Messages:</i></b> Pathogenic bacteria remarkable capacity pathogenesis. While we are beginning understand multifaceted complex adaptations occur infection, there still much uncover with research.

Language: Английский

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GlpD involved in the virulence and persistence of a marine pathogen Vibrio splendidus

Aquaculture, Journal Year: 2024, Volume and Issue: 585, P. 740691 - 740691

Published: Feb. 19, 2024

Language: Английский

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Metabolic flux regulates growth transitions and antibiotic tolerance in uropathogenic Escherichia coli

Journal of Bacteriology, Journal Year: 2024, Volume and Issue: 206(6)

Published: May 30, 2024

Reducing growth and limiting metabolism are strategies that allow bacteria to survive exposure environmental stress antibiotics. During infection, uropathogenic

Language: Английский

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