A high-throughput assay identifies molecules with antimicrobial activity against persister cells

Journal of Medical Microbiology, Год журнала: 2024, Номер 73(7)

Опубликована: Июль 12, 2024

Introduction. Persister cells are transiently non-growing antibiotic-tolerant bacteria that cause infection relapse, and there is no effective antibiotic therapy to tackle these infections. Gap statement. High-throughput assays in drug discovery biased towards detecting drugs inhibit bacterial growth rather than killing bacteria. A new simple assay discover such needed. Aim. This study aims develop a high-throughput identify compounds with antimicrobial activity against persister use it molecular motifs activity. Methodology. We quantified Staphylococcus aureus by enumeration of colony forming units after 24 h ciprofloxacin treatment. first how the cell concentration, phase presence/absence nutrients during exposure affected fraction population. After optimizing parameters, we screened compound fragments structures have cells. Results. Exponential- stationary-phase cultures transferred nutrient-rich media displayed bi-phasic time-kill curve contained 0.001–0.07% short rifampicin treatment resulted 100% for 7 h, which resumed became susceptible. Stationary-phase low but constant death rate ultimately similarly survival rates as exponential-phase The phenotype was only maintained most population if were carbon-free minimal medium before ciprofloxacin. Keeping starved enabled generation high concentrations S. tolerate 50× MIC ciprofloxacin, used this protocol rapid screening biocidal antibiotics. identified seven from four structural clusters . Two moderately cytotoxic, rest highly cytotoxic. Conclusion. Transferring culture testing strategy antibiotics kill molecule activity, further needed lower general cytotoxicity.

Язык: Английский

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Bacterial heterogeneity and antibiotic persistence: bacterial mechanisms utilized in the host environment

Microbiology and Molecular Biology Reviews, Год журнала: 2023, Номер 87(4)

Опубликована: Ноя. 14, 2023

SUMMARYAntibiotic persistence, or the ability of small subsets bacteria to survive prolonged antibiotic treatment, is an underappreciated cause treatment failure. Over past decade, researchers have discovered multiple different stress responses and mechanisms that can promote persistence. However, many these studies been completed in culture-based systems fail truly replicate complexities host environment, it unclear whether defined

Язык: Английский

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The macrophage–bacterium mismatch in persister formation

Trends in Microbiology, Год журнала: 2024, Номер 32(10), С. 944 - 956

Опубликована: Март 4, 2024

Many pathogens are hard to eradicate, even in the absence of genetically detectable antimicrobial resistance mechanisms and despite proven antibiotic susceptibility. The fraction clonal bacteria that temporarily elude effective treatments is commonly known as 'antibiotic persisters.' Over past decade, there has been a growing body research highlighting pivotal role played by cellular host development persisters. In parallel, this also sought elucidate molecular underlying formation intracellular persisters demonstrated prominent for bacterial stress response. However, questions remain regarding conditions leading stress-induced among population an ostensibly uniform environment. opinion, following brief review current state knowledge persisters, we explore ways which macrophage functional heterogeneity phenotypic may contribute emergence these We propose degree mismatch between permissiveness preparedness invade thrive intracellularly explain nonreplicating

Язык: Английский

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Type I toxin-antitoxin systems in bacteria: from regulation to biological functions

EcoSal Plus, Год журнала: 2024, Номер unknown

Опубликована: Май 20, 2024

ABSTRACT Toxin-antitoxin systems are ubiquitous in the prokaryotic world and widely distributed among chromosomes mobile genetic elements. Several different toxin-antitoxin system types exist, but what they all have common is that toxin activity prevented by cognate antitoxin. In type I systems, production controlled an RNA antitoxin structural features inherent to messenger RNA. Most toxins small membrane proteins display a variety of cellular effects. While originally discovered as modules stabilize plasmids, chromosomal may also prophages, or serve important functions upon certain stress conditions contribute population-wide survival strategies. Here, we will describe intricate RNA-based regulation discuss their potential biological functions.

Язык: 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, Год журнала: 2024, Номер 15

Опубликована: Май 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

Язык: Английский

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Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5904 - 5904

Опубликована: Май 28, 2024

For the past 70 years, dopamine hypothesis has been key working model in schizophrenia. This contributed to development of numerous inhibitors dopaminergic signaling and antipsychotic drugs, which led rapid symptom resolution but only marginal outcome improvement. Over decades, there limited research on quantifiable pathological changes schizophrenia, including premature cellular/neuronal senescence, brain volume loss, attenuation gamma oscillations electroencephalograms, oxidation lipids plasma mitochondrial membranes. We surmise that aberrant activation aryl hydrocarbon receptor by toxins derived from gut microbes or environment drives cellular neuronal a hallmark Early aging promotes secondary changes, impairment loss mitochondria, gray matter depletion, decreased oscillations, compensatory metabolic shift lactate lactylation. The aim this narrative review is twofold: (1) summarize what known about senescence schizophrenia schizophrenia-like disorders, (2) discuss novel strategies for improving long-term outcomes severe mental illness with natural senotherapeutics, membrane lipid replacement, transplantation, microbial phenazines, antioxidant phenothiazines, glycogen synthase kinase-3 beta, antagonists.

Язык: Английский

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Staphylococcus capitis : insights into epidemiology, virulence, and antimicrobial resistance of a clinically relevant bacterial species

Clinical Microbiology Reviews, Год журнала: 2024, Номер 37(3)

Опубликована: Июнь 20, 2024

SUMMARY Staphylococcus capitis is divided into two subspecies, S. subsp. ureolyticus (renamed urealyticus in 1992; ATCC 49326) and (ATCC 27840), fits with the archetype of clinically relevant coagulase-negative staphylococci (CoNS). a commensal bacterium skin humans, which must be considered an opportunistic pathogen interest particularly as soon it identified specimen from immunocompromised patient. Several studies have highlighted potential determinants underlying pathogenicity, resistance profiles, virulence factors. In addition, mobile genetic element acquisitions mutations contribute to genome adaptation its environment. Over past decades, antibiotic has been for almost all families currently available antibiotics related emergence multidrug-resistant clones high clinical significance. The present review summarizes current knowledge concerning taxonomic position among staphylococci, involvement this species human colonization diseases, factors supporting phenotypic genomic antimicrobial profiles species.

Язык: Английский

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Phagocytosis by macrophages decreases the radiance of bioluminescent Staphylococcus aureus

BMC Microbiology, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 11, 2025

In vivo evaluations of the antimicrobial efficacy biomaterials often use bioluminescent imaging modalities based on bacteria to allow follow-up in single animals. Bioluminescence production by is dependent their metabolic activity. It well known that several factors can influence metabolism bacteria, such as antimicrobials and changes bacterial growth phase. However, little about intracellular residence bioluminescence. For example, Staphylococcus aureus survive peri-implant tissue intracellularly macrophages. this study, we evaluated radiance S. upon phagocytosis We showed reduced its bioluminescence macrophages compared a culture. Simultaneously, numbers measured colony-forming units remained constant over time. was released extracellularly result macrophage cell death. Following release, increased again. Replenishment fresh an immediate increase Moreover, addition diminished decrease at 24 h coculture, but effect did not last. Together, study demonstrates decreases aureus, which important factor consider when using infection process model.

Язык: Английский

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Intracellular Staphylococcus aureus in osteoblasts and osteocytes and its impact on bone homeostasis during osteomyelitis

Bone, Год журнала: 2025, Номер 198, С. 117536 - 117536

Опубликована: Май 18, 2025

Язык: Английский

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Nutritional Stress Leads to Persistence and Persister-like Growth in Staphylococcus aureus

Pathogens, Год журнала: 2025, Номер 14(3), С. 251 - 251

Опубликована: Март 4, 2025

Staphylococcus aureus is a versatile zoonotic pathogen capable of causing wide range infections. Due to the organism’s ability persist, recalcitrant and recurring infections are major concern for public animal health. This study investigated establishment persistence using two S. strains—ATCC 29740, bovine mastitis isolate, USA300, human clinical isolate—under substrate depletion. nutritional stress established phenotype where strains remained persistent >120 days at notable concentrations [>2 log10 CFU/mL] developed persister-like growth, including small colony variant formations. With RT-qPCR, we found cell density was higher than represented by plate count while intracellular ATP constant during phase. These findings indicate that has complex survival strategies support its state, providing host-specific perspective when addressing recurrent in infectious diseases.

Язык: Английский

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