Abstract In addition to the well-known strategies of antibiotic resistance and biofilm formation, bacterial populations possess an additional survival strategy to endure hostile environments or antibiotic exposure. A small fraction of transiently antibiotic-tolerant phenotypical variants, called persister cells, is capable of surviving treatment with high doses of antibiotics. When antibiotic pressure drops, persisters that switch back to a normal phenotype can resume growth, ensuring survival of the bacterial population. Persister cells have been identified in every major pathogen, contribute to the antibiotic tolerance observed in biofilms, and are responsible for the recalcitrant nature of chronic infections. Also, evidence is accumulating that persister cells can contribute to the emergence of antibiotic resistance. Consequently, effective treatment of persister cells could greatly improve patient outcome. The small number of persisters and the redundancy in mechanisms of persister formation impede target-based development of anti-persister therapies. Nonetheless, the armory of anti-persister molecules is increasing. This review presents a comprehensive overview of anti-persister molecules and strategies described in literature to date and offers perspectives on potential anti-persistence targets and methods for the development of future therapies. Furthermore, we highlight in vivo model systems for pre-clinical testing and summarize ongoing clinical trials of candidate anti-persister therapeutics.
Last. Jan Michiels(Katholieke Universiteit Leuven)H-Index: 54
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We recently described the novel anti-persister compound 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009), capable of directly killing persister cells of the Gram-negative pathogen Pseudomonas aeruginosa. This compound also shows antibacterial effects against non-persister cells, suggesting that SPI009 could be used as an adjuvant for antibacterial combination therapy. Here, we demonstrate the broad-spectrum activity of SPI009, combined with different classes of antibiotics, against...
Last. Ying Zhang(Johns Hopkins University)H-Index: 67
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Although the majority of patients with acute Lyme disease can be cured with the standard 2-4 week antibiotic treatment, about 10-20% of patients continue suffering from chronic symptoms described as post-treatment Lyme disease syndrome (PTLDS). While the cause for this is debated, one possibility is that persister bacteria are not killed by the current Lyme antibiotics and remain active in the system. It has been reported that essential oils have antimicrobial activities and some have been used ...
Last. Myriam Cotten(W&M: College of William & Mary)H-Index: 20
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Host defense peptides (HDPs) feature evolution-tested potency against life-threatening pathogens. While piscidin 1 (p1) and piscidin 3 (p3) are homologous and potent fish HDPs, only p1 is strongly membranolytic. Here, we hypothesize that another mechanism imparts p3 strong potency. We demonstrate that the N-termini of both peptides coordinate Cu2+ and p3-Cu cleaves isolated DNA at a rate on par with free Cu2+ but significantly faster than p1-Cu. On planktonic bacteria, p1 is more antimicrobial b...
Last. Jan Michiels(Katholieke Universiteit Leuven)H-Index: 54
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ABSTRACT Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella ...
Last. Kenneth C. Keiler(PSU: Pennsylvania State University)H-Index: 24
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The emergence of Mycobacterium tuberculosis (MTB) strains that are resistant to most or all available antibiotics has created a severe problem for treating tuberculosis and has spurred a quest for new antibiotic targets. Here, we demonstrate that trans-translation is essential for growth of MTB and is a viable target for development of antituberculosis drugs. We also show that an inhibitor of trans-translation, KKL-35, is bactericidal against MTB under both aerobic and anoxic conditions. Biochem...
During microbial infection, antimicrobial peptides are utilized by the immune response to rapidly eradicate microbial pathogens through the destruction of cellular membranes. Inspired by antimicrobial peptides, quaternary ammonium cationic (QAC) compounds have emerged as agents capable of destroying bacterial membranes leading to rapid bacterial death, including the eradication of persistent, surface-attached bacterial biofilms. NH125, an imidazolium cation with a sixteen membered fatty tail, wa...
ABSTRACT Biofilms pose a unique therapeutic challenge because of the antibiotic tolerance of constituent bacteria. Treatments for biofilm-based infections represent a major unmet medical need, requiring novel agents to eradicate mature biofilms. Our objective was to evaluate bacteriophage lysin CF-301 as a new agent to target Staphylococcus aureus biofilms. We used minimum biofilm-eradicating concentration (MBEC) assays on 95 S. aureus strains to obtain a 90% MBEC (MBEC 90 ) value of ≤0.25 μg/ml...
Pseudomonas aeruginosa is a Gram-negative bacterium, which causes opportunistic infections in immuno-compromised individuals. Due to its multiple resistances toward antibiotics, the development of new drugs is required. Interfering with Quorum Sensing (QS), a cell-to-cell communication system, has shown to be highly efficient in reducing P. aeruginosa pathogenicity. One of its QS systems employs Pseudomonas Quinolone Signal (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) as signal molecules. Both ac...
Last. Sophie Helaine(Imperial College London)H-Index: 23
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Many bacteria can infect and persist inside their hosts for long periods of time. In this Review, Fisher, Gollan and Helaine discuss recent developments in our understanding of bacterial persisters and their potential implications for the treatment of persistent infections.
#1Yaqian Liu(CSU: Central South University)H-Index: 1
#2Pengfei She(CSU: Central South University)H-Index: 8
Last. Yong Wu(CSU: Central South University)H-Index: 6
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Staphylococcus aureus has increasingly attracted global attention as a major opportunistic human pathogen owing to the emergence of biofilms and persisters that are known to increase its antibiotic resistance. However, there are still no effective antimicrobial agents in clinical settings. This study investigated the antimicrobial activity of penfluridol (PF), a long-acting antipsychotic drug, against S. aureus and its clinical isolates via drug repurposing. PF exhibited strong bactericidal acti...
Last. Ming-Sound Tsao(Princess Margaret Cancer Centre)H-Index: 125
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Abstract null null A minor population of cancer cells may evade cell death from chemotherapy and targeted therapy by entering a reversible slow proliferation state known as the drug tolerant persister (DTP) state. This DTP state can allow cancer cells to survive drug therapy long enough for additional mechanisms of acquired drug resistance to develop. Thus, cancer persistence is a major obstacle to curing cancers, where insight into the biology of DTP cells and therapeutic strategies targeting t...
Last. Wei-Min Chen(JNU: Jinan University)H-Index: 15
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Abstract null null The Staphylococcus aureus can switch to a transient genotype-invariant dormancy, known as a persister, to survive treatment with high doses of antibiotics. This transient persister is an important reason underlying its resistance. There is an urgent need to find new antibacterial agents capable of eradicating methicillin-resistant S. aureus (MRSA) persisters. In this study, 37 new derivatives of cajaninstilbene acid (CSA) were designed and synthesized, and their biological act...
#2Andrew Green(U of G: University of Guelph)H-Index: 2
Last. Keith Warriner(U of G: University of Guelph)H-Index: 31
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Persisters are a form of dormancy in bacteria that provide temporary resistance to antibiotics. The following reports on the formation of Escherichia coli O157:H7 E318 Type II persisters from a protracted (8 days) challenge with ampicillin. E. coli O157:H7 followed a multi-phasic die-off pattern with an initial rapid decline (Phase I) of susceptible cells that transitioned to a slower rate representing tolerant cells (Phase II). After 24 h post-antibiotic challenge the E. coli O157: H7 levels re...
Staphylococcus aureus is considered the most common opportunistic pathogen in humans, capable of forming biofilm, increasing the chances of antibiotic resistance and causes several chronic diseases. Biodiversity is a source of inspiration in the search for new agents against these microorganisms. Hitherto, the efficacy of Hypericum sp. extracts as an antibacterial agent has already been demonstrated against Gram-positive and Gram-negative bacteria. In this study, we observed that until 4 µg/mL, ...
Toxin-antitoxin modules function in the genetic stability of mobile genetic elements, bacteriophage defense, and antibiotic tolerance. A gain-of-function mutation of the Escherichia coli K-12 hipBA module can induce antibiotic tolerance in a subpopulation of bacterial cells, a phenomenon known as persistence. HipA is a Ser/Thr kinase that phosphorylates and inactivates glutamyl tRNA synthetase, inhibiting cellular translation and inducing the stringent response. Additional characterized HipA hom...
Last. Shuming Pan(SJTU: Shanghai Jiao Tong University)
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Background: Acute lung injury and acute respiratory distress syndrome are most often caused by bacterial pneumonia, characterized by severe dyspnea and high mortality. Knowledge about the lung injury effects of current clinical bacteria strains is lacking. The aim of this study was to investigate the ability of representative pathogenic bacteria isolated from patients to cause ALI/ARDS in mice and identify the virulent factors. Method: 7 major bacteria species were isolated from clinical sputum ...
Last. Michael Hensel(University of Osnabrück)H-Index: 64
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During infectious diseases, small subpopulations of bacterial pathogens enter a non-replicating (NR) state tolerant to antibiotics. After phagocytosis, intracellular Salmonella enterica serovar Typhimurium (STM) forms persisters able to subvert immune defenses of the host. Physiological state and sensing properties of persisters are difficult to analyze, thus poorly understood. Here we deploy fluorescent protein reporters to detect intracellular NR persister cells, and to monitor their stress re...