DOCSLIB.ORG

Persister Cells, Dormancy and Infectious Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Persister Cells, Dormancy and Infectious Disease REVIEWS Persister cells, dormancy and infectious disease Kim Lewis Abstract | Several well-recognized puzzles in microbiology have remained unsolved for decades. These include latent bacterial infections, unculturable microorganisms, persister cells and biofilm multidrug tolerance. Accumulating evidence suggests that these seemingly disparate phenomena result from the ability of bacteria to enter into a dormant (non-dividing) state. The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review. Dormant Persisters were described by Joseph Bigger in 1944 in one alternative target; antibiotic modification or destruc- 1 A dormant cell has a global of the first studies on the mechanism of penicillin action . tion; antibiotic efflux; and restricted permeability to slowdown of metabolic Bigger discovered that penicillin lysed a growing popula- antibiotics9,10. It is interesting to note that all of the processes and does not divide. tion of Staphylococcus spp., but that a small number of theoretically logical possibilities of antibiotic resistance persister cells, which were not simply antibiotic-resistant seem to have been realized in nature. Importantly, all of Tolerance The ability of cells to survive mutants, inevitably survived (FIG. 1a) and proposed that these mechanisms accomplish the same aim, which is to killing by antibiotics without these were dormant, non-dividing cells. Harris Moyed prevent the antibiotic from binding to its target (FIG. 2). expressing or using resistance continued working on the problem in the 1980s and Each of these resistance mechanisms allows cells to grow mechanisms. carried out a targeted search for persister genes2–6. He at an elevated concentration of antibiotic. Bactericidal Non-proliferation treated a population of Escherichia coli with ampicillin, antibiotics kill the cell not by inhibiting the target, but A cell that does not divide. then allowed the surviving cells to grow in the absence by corrupting its function to create a toxic product. of antibiotic. After several such cycles, two colony types Aminoglycoside antibiotics kill the cell by interrupting Chaperone were identified following plating on solid media; these translation, which produces misfolded toxic peptides11. A protein that mediates the were conventional antibiotic-resistant mutants that grew Beta-lactam antibiotics, such as penicillin, inhibit pep- assembly of another polypeptide-containing in the presence of ampicillin, and mutants that produced tidoglycan synthesis, which activates, by an unknown 12 structure, but does not form persister cells at a higher frequency, but that were unable mechanism, autolysin enzymes present in the cell wall . part of the completed to grow in the presence of ampicillin. This leads to digestion of the peptidoglycan by autolysins structure, or participate in its One of these persister mutations was mapped to and cell death. Fluoroquinolones inhibit the ligase step of biological function. the hipA gene. The hipA7 allelic strain produced ~1% the DNA gyrase and topoisomerase, without affecting the persisters that survived treatment with ampicillin in preceding nicking activity. As a result, the enzymes are exponential cultures, which is approximately 1,000 times converted into endonucleases13. more persisters than the wild-type strain. In contrast to resistance, the tolerance of persisters to The recent discovery of persisters in biofilms7,8 has antibiotics might function by preventing target corruption rekindled interest in these unusual cells. Indeed, the pres- by a bactericidal agent through the blocking of the anti- ence of persister cells might be important in the aetiology biotic target(s) (FIG. 2). If persisters are dormant and have of many recalcitrant infectious diseases. In this Review, little or no cell-wall synthesis, translation or topoisomer- I will summarize the biology of persister cells and offer ase activity, then the antibiotics will bind to, but will be insights into their role in infectious disease. unable to corrupt, the function of their target molecules. Antimicrobial Discovery In this way tolerance could enable resistance to killing by Center and Department of Biology, Northeastern Multidrug resistance and multidrug tolerance antibiotics, but at the price of non-proliferation. University, 360 Huntington Numerous mechanisms of drug resistance have been Avenue, Boston, described, and in most cases we have a good under- Production of persister cells Massachusetts, 02115 USA. standing of these processes at the molecular level. The The simplest route to form a dormant persister cell e-mail: [email protected] doi:10.1038/nrmicro1557 main types of resistance are target modification by might be through the overproduction of proteins that are Published online mutation; target modification by specialized enzymatic toxic to the cell and inhibit growth. Recombinant E. coli 4 December 2006 changes; target substitution, such as expressing an cells that overproduce the chaperone DnaJ, or the PmrC 48 | JANUARY 2007 | VOLUME 5 www.nature.com/reviews/micro © 2007 Nature Publishing Group REVIEWS a unpublished observations). Whatever the mechanism, Antibiotic added the dynamics of persister formation provide an inter- 10 Regular esting insight into this strategy of persistence. Because cells 8 the highest frequency of persister formation occurs –1 Persisters 6 Resistant in the stationary phase of growth their main function mutants might be to ensure the survival of this non-growing 4 population. As persisters do not grow, it would seem Log CFU ml 2 logical for the entire stationary population to enter into this protected survival state, but this is not the 0 02468101214 case. The benefit of being a regular, dividing cell seems Time (h) to stem from its ability to rapidly resume growth, a b process that takes 1–1.5 hours longer for a dormant Lag phase Stationary phase persister cell16. Because most cells in an E. coli or Early exponential P. ae r ug ino s a stationary phase population are non- phase persisters, this indicates that the optimal individual 10 Growth strategy is not to enter into persistence, suggesting 8 Persisters –1 that the persister state is an altruistic behaviour 6 benefiting the kin. Indeed, in the rare instance that the whole population of normal cells is killed by a 4 lethal factor, the surviving persisters can propagate the Log CFU ml 2 genome that they share with their kin (BOX 1). 0 02468101214 Genetics of persister formation Time (h) Attempts to identify genes that are required for persister- Figure 1 | Formation of persister cells. a | Shows the cell formation by transposon mutagenesis were unsuc- 17,18 treatment of a population with an antibiotic, which results cessful . Such experiments are problematic owing to in cell death, leaving only persister cells or resistant the variation in the numbers of persisters identified in mutants alive. b | Shows the frequency of isolation of parallel replicates19, which leads to an unmanageable persisters as a function of the growth phase of the culture. level of false-positives and false-negatives when screen- ing a large library. An alternative method is to identify genes by gain-of-function from an expression library. protein from Salmonella entericia serovar Typhimurium However, overproduction of some proteins can result (S. typhimurium), stopped growing and became highly in toxic effects that restrict cell growth, which results tolerant to ampicillin and ciprofloxacin14. in the isolation of false-positives. It seems that standard However, this simple mechanism is unlikely to be genetic approaches are poorly suited to searching for responsible for the natural production of persisters. persister genes. Examination of the rate of E. coli persister-cell formation over time showed that few of these cells are formed in a early exponential phase, followed by a sharp increase in persister-cell formation in mid-exponential phase, + Cell death reaching a maximum of ~1% of cells forming persisters in the non-growing stationary phase (FIG. 1b). In order Antibiotic Target Target corrupted to probe whether persisters isolated during the early exponential phase of growth were introduced from b a stationary state culture inoculum, or were formed de novo, the culture was kept in early exponential + Resistance phase by repeated dilution and regrowth15. After four cycles, persister cells completely disappeared. This simple experiment rules out non-specific mechanisms c Quorum sensing The ability of bacteria to sense of persister formation and indicates that persister cells their own cell density by are preformed, rather than being produced in response + Tolerance detecting the concentration of to antibiotics. signalling molecules that have The formation of persisters rapidly increases during been released in their mid-exponential phase in several species, but the mecha- Figure 2 | Resistance versus tolerance to bactericidal environment. antibiotics. a | The antibiotic (pink) binds to the target nism that underlies this remains a puzzle. Quorum sensing (blue) altering its function, which causes cell death. b | The does not seem to have a role in persister formation, Signalling molecule target of the antibiotic has been altered so that it fails to A chemical, similar to a because the addition of spent growth medium (which bind the antibiotic and the cell becomes resistant to pheromone, that is produced would contain high concentrations of quorum-sensing by an individual
Load more

Recommended publications
  • Use of Ceragenins As a Potential Treatment for Urinary Tract Infections Urszula Wnorowska1, Ewelina Piktel1, Bonita Durnaś2, Krzysztof Fiedoruk3, Paul B
    Wnorowska et al. BMC Infectious Diseases (2019) 19:369 https://doi.org/10.1186/s12879-019-3994-3 RESEARCH ARTICLE Open Access Use of ceragenins as a potential treatment for urinary tract infections Urszula Wnorowska1, Ewelina Piktel1, Bonita Durnaś2, Krzysztof Fiedoruk3, Paul B. Savage4 and Robert Bucki1* Abstract Background: Urinary tract infections (UTIs) are one of the most common bacterial infections. High recurrence rates and the increasing antibiotic resistance among uropathogens constitute a large social and economic problem in current public health. We assumed that combination of treatment that includes the administration ceragenins (CSAs), will reinforce the effect of antimicrobial LL-37 peptide continuously produced by urinary tract epithelial cells. Such treatment might be an innovative approach to enhance innate antibacterial activity against multidrug- resistant E. coli. Methods: Antibacterial activity measured using killing assays. Biofilm formation was assessed using crystal violet staining. Viability of bacteria and bladder epithelial cells subjected to incubation with tested agents was determined using MTT assays. We investigated the effects of chosen molecules, both alone and in combinations against four clinical strains of E. coli, obtained from patients diagnosed with recurrent UTI. Results: We observed that the LL-37 peptide, whose concentration increases at sites of urinary infection, exerts increased bactericidal effect against E. coli when combined with ceragenins CSA-13 and CSA-131. Conclusion: We suggest that the employment of combination of natural peptide LL-37 with synthetic analogs might be a potential solution to treat urinary tract infections caused by drug-resistant bacteria. Keywords: Urinary tract infection, LL-37 peptide, Ceragenins, Bacterial drug resistance Background trimethoprim/sulphamethoxazole, may no longer be used Urinary tract infections (UTIs) are one of the most com- for empiric treatment due to high resistance rates [7].
    [Show full text]
  • Antimicrobials: Killing Persisters While They Sleep
    RESEARCH HIGHLIGHTS ANTIMICROBIALS Killing persisters while they sleep Bacterial persisters are a certain metabolites can enhance of mannitol enhanced gentamicin subpopulation of dormant cells the killing of both Gram-negative killing of persister cells by more than that have been implicated in a and Gram-positive persisters by two orders of magnitude. Similarly, it may be possible range of chronic and recurrent aminoglycosides. in mice that were implanted with to eradicate infections through their ability Aminoglycoside uptake into the catheters which had been colonized bacterial to survive antibiotic treatments. bacterium is energy dependent, by a uropathogenic E. coli strain, Although most cellular processes are leading the authors to investigate administration of mannitol together persisters in a completely shut down in persisters, whether metabolic stimulation with gentamicin reduced the viability clinical setting translation still occurs, albeit at a enhances the killing of persister of biofilm bacteria on the catheter by stimulating reduced rate, making the use of cells by increasing the uptake of by more than an order of magnitude. their underlying aminoglycoside antibiotics (which these antibiotics. They found that Finally, the authors tested whether metabolic activity target the ribosome) an attractive the addition of glucose, mannitol, metabolite addition enhanced option. However, aminoglycosides fructose or pyruvate increased the aminoglycoside killing of Gram- concurrently have only weak activity against this killing of isolated Escherichia coli positive bacteria; whereas mannitol, with antibiotic subpopulation of cells. Writing persisters by gentamicin, kanamycin glucose and pyruvate had no effect, treatment. in Nature, Collins and colleagues and streptomycin by more than three the addition of fructose enhanced now show that the addition of orders of magnitude.
    [Show full text]
  • Mechanisms of Staphylococcus Aureus Persistence And
    MECHANISMS OF STAPHYLOCOCCUS AUREUS PERSISTENCE AND ERADICATION OF CHRONIC STAPHYLOCOCCAL INFECTIONS by Rebecca Yee A dissertation submitted to the Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland December, 2018 ABSTRACT Bacteria can exist in different phenotypic states depending on environmental conditions. Under stressed conditions, such as antibiotic exposure, bacteria can develop into persister cells that allow them to stay dormant until the stress is removed, when they can revert back to a growing state. The interconversion of non-growing persister cells and actively growing cells is the underlying basis of relapsing and chronic persistent infections. Eradication and better treatment of chronic, persistent infections caused by Staphylococcus aureus requires a multi- faceted approach, including a deeper understanding of how the bacteria persist under stressed conditions, regulate its cell death pathways, and development of novel drug therapies. Persisters were first discovered in the 1940s in a staphylococcal culture in which penicillin failed to kill a small subpopulation of the cells. Despite the discovery many decades ago, the specific mechanisms of Staphylococcus aureus persistence is largely unknown. Recently renewed interest has emerged due to the rise of chronic infections caused by pathogens such as M. tuberculosis, B. burgdorferi, S. aureus, P. aeruginosa, and E. coli. Treatments for chronic infections are lacking and antibiotic resistance is becoming a bigger issue. The goal of our research is to define the mechanisms involved in S. aureus persistence and cell death to improve our knowledge of genes and molecular pathways that can be used as targets for drugs to eradicate chronic infections.
    [Show full text]
  • Eradication of Bacterial Persisters with Antibiotic-Generated Hydroxyl Radicals
    Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals Sarah Schmidt Grant a,b,c,1, Benjamin B. Kaufmanna,c,d,1, Nikhilesh S. Chandd,e, Nathan Haseleya,d,f, and Deborah T. Hunga,b,c,d,2 aBroad Institute of MIT and Harvard, Cambridge, MA 02142; bDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02114; cDepartment of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; dDepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; eDepartment of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; and fHarvard–MIT Division of Health Sciences and Technology, Cambridge, MA 02139 Edited by* Eric S. Lander, Broad Institute of MIT and Harvard, Cambridge, MA, and approved June 11, 2012 (received for review March 2, 2012) During Mycobacterium tuberculosis infection, a population of bac- terial cell numbers but do not sterilize the mouse (8). A plateau teria likely becomes refractory to antibiotic killing in the absence of is typically reached during which numbers of viable bacteria genotypic resistance, making treatment challenging. We describe stabilize. In addition to the mouse infection model, the inability an in vitro model capable of yielding a phenotypically antibi- to sterilize has been observed in the zebra fish (Mycobacterium otic-tolerant subpopulation of cells, often called persisters, within marinum), guinea pig (M. tuberculosis), and macrophage populations of Mycobacterium smegmatis and M. tuberculosis.We (M. tuberculosis) infection models (9–11). In vitro, the survival find that persisters are distinct from the larger antibiotic-suscepti- of a similar small subpopulation can also be observed when ble population, as a small drop in dissolved oxygen (DO) satura- a culture is exposed to high doses of antibiotics (12, 13).
    [Show full text]
  • Phenol-Soluble Modulins Modulate Persister Cell Formation In
    Phenol-Soluble Modulins Modulate Persister Cell Formation in Staphylococcus aureus Baldry, Mara; Bojer, Martin S; Najarzadeh, Zahra; Vestergaard, Martin; Meyer, Rikke Louise; Otzen, Daniel Erik; Ingmer, Hanne Published in: Frontiers in Microbiology DOI: 10.3389/fmicb.2020.573253 Publication date: 2020 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Baldry, M., Bojer, M. S., Najarzadeh, Z., Vestergaard, M., Meyer, R. L., Otzen, D. E., & Ingmer, H. (2020). Phenol-Soluble Modulins Modulate Persister Cell Formation in Staphylococcus aureus. Frontiers in Microbiology, 11, 573253. https://doi.org/10.3389/fmicb.2020.573253 Download date: 23. sep.. 2021 ORIGINAL RESEARCH published: 09 November 2020 doi: 10.3389/fmicb.2020.573253 Phenol-Soluble Modulins Modulate Persister Cell Formation in Staphylococcus aureus Mara Baldry 1†, Martin S. Bojer 1, Zahra Najarzadeh 2, Martin Vestergaard 1, Rikke Louise Meyer 2, Daniel Erik Otzen 2 and Hanne Ingmer 1* 1Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark, 2Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark Edited by: Thomas Keith Wood, Pennsylvania State University (PSU), Staphylococcus aureus is a human pathogen that can cause chronic and recurrent United States infections and is recalcitrant to antibiotic chemotherapy. This trait is partly attributed to Reviewed by: Jie Feng, its ability to form persister cells, which are subpopulations of cells that are tolerant to lethal Lanzhou University Medical College, concentrations of antibiotics. Recently, we showed that the phenol-soluble modulins China (PSMs) expressed by S. aureus reduce persister cell formation.
    [Show full text]
  • Persister Cells Form in the Plant Pathogen Xanthomonas Citri Subsp
    microorganisms Article Persister Cells Form in the Plant Pathogen Xanthomonas citri subsp. citri under Different Stress Conditions Paula M. M. Martins 1,2 , Thomas K. Wood 1,* and Alessandra A. de Souza 2,* 1 Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802, USA; [email protected] 2 Biotechnology Laboratory, Centro de Citricultura Sylvio Moreira, Instituto Agronômico de Campinas, Rodovia Anhanguera Km 158, Cordeirópolis-SP 13490-000, Brazil * Correspondence: [email protected] (T.K.W.); [email protected] (A.A.d.S.) Abstract: Citrus canker disease, caused by the bacterium Xanthomonas citri subsp. citri is a constant threat to citrus-producing areas. Since it has no cure, agricultural practices to restrain its dissemination are essential to reduce the economic damage. Hence, increased knowledge of the basic aspects of X. citri biology could lead to more efficient management practices that can eliminate dormant bacteria in the field. The dormant cells, also referred to as persisters, are phenotypic variants with lowered metabolism, which in turn leads to tolerance to antimicrobials and undermines existing control approaches. We show here that X. citri forms persisters, identifying triggers for this phenotype, including antibiotics, high temperature, and metals (copper and zinc), which increase persistence rates by 10–100 times. The antioxidant N-acetylcysteine reduced copper and zinc-induced persisters, but not those induced by tetracycline, indicating that oxidative stress may be an important inducer of X. citri persistence. In addition, we found that metabolism-independent drugs like cisplatin and mitomycin C are able to eliminate X. citri persistent cells, as well as copper, at high concentrations.
    [Show full text]
  • Controlling Bacterial Persister Cells and Biofilms by Synthetic Brominated Furanones
    Syracuse University SURFACE Biomedical and Chemical Engineering - Dissertations College of Engineering and Computer Science 8-2013 Controlling Bacterial Persister Cells and Biofilms yb Synthetic Brominated Furanones Jiachuan Pan Follow this and additional works at: https://surface.syr.edu/bce_etd Part of the Chemical Engineering Commons Recommended Citation Pan, Jiachuan, "Controlling Bacterial Persister Cells and Biofilms yb Synthetic Brominated Furanones" (2013). Biomedical and Chemical Engineering - Dissertations. 68. https://surface.syr.edu/bce_etd/68 This Dissertation is brought to you for free and open access by the College of Engineering and Computer Science at SURFACE. It has been accepted for inclusion in Biomedical and Chemical Engineering - Dissertations by an authorized administrator of SURFACE. For more information, please contact [email protected]. ABSTRACT Bacteria are well known to obtain tolerance to antibiotics by forming multicellular structures, known as biofilms, and by entering dormancy and forming persister cells. Both mechanisms allow bacteria to tolerate antibiotics at concentrations hundreds to thousands of times higher than the lethal dose for regular planktonic cells of the same genotype. Persister formation increases in biofilms; thus, effective control of persister cells, especially those in biofilms is critically important to infection control. Over the past decades, a bacterial signaling system based on cell density, named quorum sensing (QS), has been found to regulate biofilm formation and, in Pseudomonas aeruginosa , the level of persistence. In this study, we characterized the effects of synthetic brominated furanones, a group of QS inhibitors, on the persistence of P. aeruginosa and Escherichia coli . Our results revealed that (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5 H)-one (BF8) can reduce persister formation in P.
    [Show full text]
  • Characterization of Persister Cells and Some Mutants from Clinical Isolate of a Multidrug-Resistant MRSA
    769 International Journal of Progressive Sciences and Technologies (IJPSAT) ISSN: 2509-0119. © 2020 International Journals of Sciences and High Technologies http://ijpsat.ijsht-journals.org Vol. 22 No. 1 August 2020, pp. 127-135 Characterization of Persister Cells and Some Mutants from Clinical Isolate of a Multidrug-Resistant MRSA Sally ElSheikh1, Hamdia Askar2 and Yehia A. Osman*1 1 Botany Department, Faculty of Science 2 Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, 35166, Egypt Abstract – Background: Some multidrug resistant bacteria such as MRSA, produce persister cells in the presence of bactericidal agents, which enables them to survive in the presence of the antibiotics. Evolution of persisters and the mechanisms of survival are still debatable and difficult to understand. Formation of persister cells establishes phenotypic heterogeneity within a bacterial population, causes relapses of bacterial infections and linked to failed treatments and the emergence of antibiotic resistance. Method: MRSA-derived persisters were isolated under vancomycin stress and mutated by exposure to ultraviolet radiation; 254um. Persister cells and the mutants were classically and biochemically characterized. Persister cells were further subjected to persister's assay, grown on Baird-Parker medium, tested for biofilm formation, DNase production and mannitol fermentation. Results: Bacteriologically and biochemically persisters were found to be similar to the clinical isolate and standard MRSA strains. But distinctive differences were observable in the DNase, coagulase and catalase activities. Conclusion: A general method for isolating persisters was developed based on lysis of regular MRSA cells by vancomycin. These persisters retained all MRSA characteristics but shown down regulated enzyme activities. Keywords – S.
    [Show full text]
  • Identification of a Toxin–Antitoxin System That Contributes to Persister Formation by Reducing NAD in Pseudomonas Aeruginosa
    microorganisms Article Identification of a Toxin–Antitoxin System That Contributes to Persister Formation by Reducing NAD in Pseudomonas aeruginosa Jingyi Zhou, Shouyi Li, Haozhou Li, Yongxin Jin, Fang Bai , Zhihui Cheng and Weihui Wu * State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China; [email protected] (J.Z.); [email protected] (S.L.); [email protected] (H.L.); [email protected] (Y.J.); [email protected] (F.B.); [email protected] (Z.C.) * Correspondence: [email protected] Abstract: Bacterial persisters are slow-growing or dormant cells that are highly tolerant to bactericidal antibiotics and contribute to recalcitrant and chronic infections. Toxin/antitoxin (TA) systems play important roles in controlling persister formation. Here, we examined the roles of seven predicted type II TA systems in the persister formation of a Pseudomonas aeruginosa wild-type strain PA14. Overexpression of a toxin gene PA14_51010 or deletion of the cognate antitoxin gene PA14_51020 increased the bacterial tolerance to antibiotics. Co-overexpression of PA14_51010 and PA14_51020 or simultaneous deletion of the two genes resulted in a wild-type level survival rate following antibiotic Citation: Zhou, J.; Li, S.; Li, H.; treatment. The two genes were located in the same operon that was repressed by PA14_51020. Jin, Y.; Bai, F.; Cheng, Z.; Wu, W. We further demonstrated the interaction between PA14_51010 and PA14_51020. Sequence analysis Identification of a Toxin–Antitoxin revealed that PA14_51010 contained a conserved RES domain.
    [Show full text]
  • The Antimicrobial Peptide Temporin G: Anti-Biofilm, Anti-Persister
    International Journal of Molecular Sciences Article The Antimicrobial Peptide Temporin G: Anti-Biofilm, Anti-Persister Activities, and Potentiator Effect of Tobramycin Efficacy Against Staphylococcus aureus Bruno Casciaro 1,* , Maria Rosa Loffredo 2, Floriana Cappiello 2, Guendalina Fabiano 2, Luisa Torrini 2 and Maria Luisa Mangoni 2,* 1 Center For Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy 2 Laboratory Affiliated to Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical Sciences, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; mariarosa.loff[email protected] (M.R.L.); fl[email protected] (F.C.); [email protected] (G.F.); [email protected] (L.T.) * Correspondence: [email protected] (B.C.); [email protected] (M.L.M.); Tel.: +39-0649910838 (M.L.M.) Received: 16 November 2020; Accepted: 8 December 2020; Published: 10 December 2020 Abstract: Bacterial biofilms are a serious threat for human health, and the Gram-positive bacterium Staphylococcus aureus is one of the microorganisms that can easily switch from a planktonic to a sessile lifestyle, providing protection from a large variety of adverse environmental conditions. Dormant non-dividing cells with low metabolic activity, named persisters, are tolerant to antibiotic treatment and are the principal cause of recalcitrant and resistant infections, including skin infections. Antimicrobial peptides (AMPs) hold promise as new anti-infective agents to treat such infections. Here for the first time, we investigated the activity of the frog-skin AMP temporin G (TG) against preformed S. aureus biofilm including persisters, as well as its efficacy in combination with tobramycin, in inhibiting S.
    [Show full text]
  • Biofilm and Persister Cell Fo Mation Variability in Clinical Isolates of Klebsiella Pneumoniae in Colombia
    Univ. Sci. 25 (3): 545-571, 2020. doi: 10.11144/Javeriana.SC25-3.dpbo Bogotá ORIGINAL ARTICLE Biofilm and persister cell fo mation variability in clinical isolates of Klebsiella pneumoniae in Colombia Leonardo Posada1, Iván C. Acosta1, 2, Lina Zárate1, 3, Paula Rodríguez1, Mónica Gabriela Huertas1, 4, María Mercedes Zambrano1, 5, * Abstract Edited by Juan Carlos Salcedo-Reyes ([email protected]) Klebsiella pneumoniae is an opportunistic pathogen associated with nosocomial infections. Persister cells are a fraction of a bacterial 1. Corporación Corpogen Bogotá, Colombia, 110311. population that can escape antibiotic treatment and are associated 2. National Center for Biotechnology, with antibiotic therapy failure. In this work, we analyzed persistent Madrid, Spain, 28049. cells in planktonic cultures and biofilms using 10 K. pneumoniae 3. Max Planck Institute for Infection clinical isolates and four different antibiotic types. The isolates had Biology, Berlin, Germany, 10117. 4. Universidad El Bosque, Faculty of different antibiotic susceptibility profiles that did not correlate with Medicine, Bogotá, Colombia, 110121. their capacity to form biofilms. Persister cells were found under all 5. Universidad Central, Bogotá, Colombia, conditions tested, although their population numbers varied depending 110311. on the antibiotic used. A larger number of persister cells were * [email protected] found in biofilms than in planktonic cultures. Antibiotic treatment Received: 12-09-2019 with trimethoprim-sulfamethoxazole resulted in the largest persister Accepted: 07-09-2020 Published on line: 31-12-2020 cell sub-population compared with other antibiotics tested, while ciprofloxacin was the antibiotic that produced fewer persister cells. These Citation: Posada L, Acosta IC, Zárate results indicate that K.
    [Show full text]
  • Bacterial Persister Cell Formation and Dormancy
    MINIREVIEW Bacterial Persister Cell Formation and Dormancy Thomas K. Wood,a,b Stephen J. Knabel,c Brian W. Kwana Department of Chemical Engineering,a Department of Biochemistry and Molecular Biology,b and Department of Food Science,c The Pennsylvania State University, University Park, Pennsylvania, USA Bacterial cells may escape the effects of antibiotics without undergoing genetic change; these cells are known as persisters. Unlike resistant cells that grow in the presence of antibiotics, persister cells do not grow in the presence of antibiotics. These persister cells are a small fraction of exponentially growing cells (due to carryover from the inoculum) but become a significant fraction in the stationary phase and in biofilms (up to 1%). Critically, persister cells may be a major cause of chronic infections. The mecha- nism of persister cell formation is not well understood, and even the metabolic state of these cells is debated. Here, we review studies relevant to the formation of persister cells and their metabolic state and conclude that the best model for persister cells is still dormancy, with the latest mechanistic studies shedding light on how cells reach this dormant state. PERSISTER CELLS AND INFECTION nas aeruginosa, S. aureus, Lactobacillus acidophilus, and Gardner- ella vaginalis (7). ersister cells, those cells tolerant to antibiotics, usually com- Note that the rate at which persisters form is a function of prise about 1% in the stationary state and in biofilms (1, 2). P inoculum age in that older inocula have more persister cells (8). These persister cells arise due to a state of dormancy, defined here Hence, if older inocula are used, there is little difference between as a state in which cells are metabolically inactive.
    [Show full text]