scholarly journals Bacteriophage treatment before chemical disinfection can enhance removal of plastic surface-associated Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Elyse Stachler ◽  
Anina Kull ◽  
Timothy R. Julian
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Built Environment ◽  
Sodium Hypochlorite ◽  
Benzalkonium Chloride ◽  
Opportunistic Pathogen ◽  
Opportunistic Pathogens ◽  
Antibiotic Resistant ◽  
Chemical Disinfectant ◽  
Chemical Disinfection ◽  
Phage Treatment

Opportunistic pathogens can linger on surfaces in hospital and building plumbing environments, leading to infections in at-risk populations. Further, biofilm-associated bacteria are protected from removal and inactivation protocols, such as disinfection. Bacteriophages show promise as tools to treat antibiotic resistant infections. As such, phages may also be useful in environmental applications to prevent newly acquired infections. In the current study, the potential of synergies between bacteriophage and chemical disinfection of the opportunistic pathogen Pseudomonas aeruginosa was assessed under various conditions. Specifically, surface-associated P. aeruginosa was treated with various concentrations of phages (P1 or JG004), chemical disinfectant (sodium hypochlorite or benzalkonium chloride), or combined sequential treatments under three distinct attachment models (spot inoculations, dry biofilms, and wet biofilms). Phages were very effective at removing bacteria in spot inoculation (>3.2 log 10 removal) and wet biofilms (up to 2.6 log 10 removal), while phages prevented regrowth of dry biofilms in the application time. In addition, phage treatment followed by chemical disinfection inactivated more P. aeruginosa under wet biofilm conditions better than either treatment alone. This effect was hindered when chemical disinfection was applied first, followed by phage treatment, suggesting additive benefits of combination treatments are lost when phage is applied last. Further, we confirm prior evidence of greater phage tolerance to benzalkonium chloride relative to sodium hypochlorite, informing choices for combination phage-disinfectant approaches. Overall, this paper further supports the potential of using combination phage and chemical disinfectant treatments to improve inactivation of surface-associated P. aeruginosa . Importance Phages are already utilized in the healthcare industry to treat antibiotic resistant infections, such as on implant-associated biofilms and in compassionate care cases. Phage treatment could also be a promising new tool to control pathogens in the built environment, preventing infections from occurring. This study shows that phage can be combined effectively with chemical disinfectants to improve removal of wet biofilms and bacteria spotted onto surfaces while preventing regrowth in dry biofilms. This has the potential to improve pathogen containment within the built environment and drinking water infrastructure to prevent infections of opportunistic pathogens.

scholarly journals Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics

2020 ◽  
Author(s):  
Lucas A. Meirelles ◽  
Elena K. Perry ◽  
Megan Bergkessel ◽  
Dianne K. Newman
Keyword(s):  
Antibiotic Resistance ◽  
Opportunistic Pathogen ◽  
Antimicrobial Treatment ◽  
Bacterial Survival ◽  
Human Pathogens ◽  
Opportunistic Pathogens ◽  
Chronic Infections ◽  
Antibiotic Resistant ◽  
Lung Infections ◽  
Environmental Microbes

SummaryAs antibiotic-resistant infections become increasingly prevalent worldwide, understanding the factors that lead to antimicrobial treatment failure is essential to optimizing the use of existing drugs. Opportunistic human pathogens in particular typically exhibit high levels of intrinsic antibiotic resistance and tolerance1, leading to chronic infections that can be nearly impossible to eradicate2. We asked whether the recalcitrance of these organisms to antibiotic treatment could be driven in part by their evolutionary history as environmental microbes, which frequently produce or encounter natural antibiotics3,4. Using the opportunistic pathogen Pseudomonas aeruginosa as a model, we demonstrate that the self-produced natural antibiotic pyocyanin (PYO) activates bacterial defenses that confer collateral tolerance to certain synthetic antibiotics, including in a clinically-relevant growth medium. Non-PYO-producing opportunistic pathogens isolated from lung infections similarly display increased antibiotic tolerance when they are co-cultured with PYO-producing P. aeruginosa. Furthermore, we show that beyond promoting bacterial survival in the presence of antibiotics, PYO can increase the apparent rate of mutation to antibiotic resistance by up to two orders of magnitude. Our work thus suggests that bacterial production of natural antibiotics in infections could play an important role in modulating not only the immediate efficacy of clinical antibiotics, but also the rate at which antibiotic resistance arises in multispecies bacterial communities.

scholarly journals F-type Pyocins are Diverse Non-Contractile Phage Tail-Like Weapons for Killing Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Senjuti Saha ◽  
Chidozie D. Ojobor ◽  
Erik Mackinnon ◽  
Olesia I. North ◽  
Joseph Bondy-Denomy ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bactericidal Activity ◽  
Pathogenic Bacteria ◽  
Therapeutic Potential ◽  
Experimental Studies ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Antibiotic Resistant ◽  
Genes Encoding ◽  
Intraspecies Competition

ABSTRACTMost Pseudomonas aeruginosa strains produce bacteriocins derived from contractile or non-contractile phage tails known as R-type and F-type pyocins, respectively. These bacteriocins possess strain-specific bactericidal activity against P. aeruginosa and likely increase evolutionary fitness through intraspecies competition. R-type pyocins have been studied extensively and show promise as alternatives to antibiotics. Although they have similar therapeutic potential, experimental studies on F-type pyocins are limited. Here, we provide a bioinformatic and experimental investigation of F-type pyocins. We introduce a systematic naming scheme for genes found in R- and F-type pyocin operons and identify 15 genes invariably found in strains producing F-type pyocins. Five proteins encoded at the 3’-end of the F-type pyocin cluster are divergent in sequence, and likely determine bactericidal specificity. We use sequence similarities among these proteins to define 11 distinct F-type pyocin groups, five of which had not been previously described. The five genes encoding the variable proteins associate in two modules that have clearly re-assorted independently during the evolution of these operons. These proteins are considerably more diverse than the specificity-determining tail fibers of R-type pyocins, suggesting that F-type pyocins emerged earlier or have been subject to distinct evolutionary pressures. Experimental studies on six F-type pyocin groups show that each displays a distinct spectrum of bactericidal activity. This activity is strongly influenced by the lipopolysaccharide O-antigen type, but other factors also play a role. F-type pyocins appear to kill as efficiently as R-type pyocins. These studies set the stage for the development of F-type pyocins as anti-bacterial therapeutics.IMPORTANCEPseudomonas aeruginosa is an opportunistic pathogen that causes a broad spectrum of antibiotic resistant infections with high mortality rates, particularly in immunocompromised individuals and cystic fibrosis patients. Due to the increasing frequency of multidrug-resistant P. aeruginosa infections, there is great interest in the development of alternative therapeutics. One alternative is protein-based antimicrobials called bacteriocins, which are produced by one strain of bacteria to kill other strains. In this study, we investigate F-type pyocins, bacteriocins naturally produced by P. aeruginosa that resemble non-contractile phage tails. We show that they are potent killers of P. aeruginosa, and distinct pyocin groups display different killing specificities. We have identified the probable specificity determinants of F-type pyocins, which opens up the potential to engineer them to precisely target strains of pathogenic bacteria. The resemblance of F-type pyocins to well characterized phage tails will greatly facilitate their development into effective antibacterials.

scholarly journals An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Valerie J Morley ◽  
Clare L Kinnear ◽  
Derek G Sim ◽  
Samantha N Olson ◽  
Lindsey M Jackson ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Bile Acid ◽  
Gastrointestinal Tract ◽  
Adjunctive Therapy ◽  
Opportunistic Pathogen ◽  
Proof Of Concept ◽  
Opportunistic Pathogens ◽  
Intravenous Antibiotic ◽  
Antibiotic Resistant ◽  
Fecal Shedding

A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.

scholarly journals Genomic and phenotypic comparison of environmental and patient-derived isolates ofPseudomonas aeruginosasuggest that antimicrobial resistance is rare within the environment

2019 ◽  
Author(s):  
Kay A Ramsay ◽  
Samuel J T Wardell ◽  
Wayne M Patrick ◽  
Ben Brockway ◽  
David W Reid ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Genetic Variants ◽  
Susceptibility Testing ◽  
Opportunistic Pathogen ◽  
Sequence Variants ◽  
Whole Genome ◽  
Environmental Isolates ◽  
Antibiotic Resistant ◽  
Environmental Bacteria

AbstractPatient-derived isolates of the opportunistic pathogenPseudomonas aeruginosaare frequently resistant to antibiotics due to the presence of sequence variants in resistance-associated genes. However, the frequency of antibiotic resistance and of resistance-associated sequence variants in environmental isolates ofP. aeruginosahas not been well studied. Antimicrobial susceptibility testing (ciprofloxacin, ceftazidime, meropenem, tobramycin) of environmental (n=50) and cystic fibrosis (n=42)P. aeruginosaisolates was carried out. Following whole genome sequencing of all isolates, twenty-five resistance-associated genes were analysed for the presence of likely function-altering sequence variants. Environmental isolates were susceptible to all antibiotics with one exception, whereas patient-derived isolates had significant frequencies of resistance to each antibiotic and a greater number of likely resistance-associated genetic variants. These findings indicate that the natural environment does not act as a reservoir of antibiotic-resistantP. aeruginosa, supporting a model in which antibiotic susceptible environmental bacteria infect patients and develop resistance during infection.Author Contributions

Exploration of the Pharmacodynamics for Pseudomonas aeruginosa Biofilm Eradication by Tobramycin

2021 ◽  
Author(s):  
Devin Sindeldecker ◽  
Shaurya Prakash ◽  
Paul Stoodley
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Treatment Duration ◽  
Area Under The Curve ◽  
Opportunistic Pathogen ◽  
Multi Drug Resistance ◽  
Antibiotic Concentration ◽  
Antibiotic Resistant ◽  
Gram Negative

Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen which is involved in numerous infections. It is of growing concern within the field of antibiotic resistant and tolerance and often exhibits multi-drug resistance. Previous studies have shown the emergence of antibiotic resistant and tolerant variants within the zone of clearance of a biofilm lawn after exposure to aminoglycosides. As concerning as the tolerant variant emergence is, there was also a zone of killing (ZOK) immediately surrounding the antibiotic source from which no detectable bacteria emerged or were cultured. In this study, the ZOK was analyzed using both in vitro and in silico methods to determine if there was a consistent antibiotic concentration versus time constraint (area under the curve, (AUC)) which is able to completely kill all bacteria in the lawn biofilms in our in vitro model. Our studies revealed that by achieving an average AUC of 4,372.5 μg*hr/mL, complete eradication of biofilms grown on both agar and hydroxyapatite was possible. These findings show that appropriate antibiotic concentrations and treatment duration may be able to treat antibiotic resistant and tolerant biofilm infections.

scholarly journals An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen

2020 ◽  
Author(s):  
Valerie J. Morley ◽  
Clare L. Kinnear ◽  
Derek G. Sim ◽  
Samantha N. Olson ◽  
Lindsey M. Jackson ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Gastrointestinal Tract ◽  
Mouse Model ◽  
Adjunctive Therapy ◽  
Opportunistic Pathogen ◽  
Proof Of Concept ◽  
Opportunistic Pathogens ◽  
Intravenous Antibiotic ◽  
Antibiotic Resistant ◽  
Fecal Shedding

AbstractA key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.

scholarly journals A Cationic Porphyrin, ZnPor, Disassembles Pseudomonas aeruginosa Biofilm Matrix, Kills Cells Directly, and Enhances Antibiotic Activity of Tobramycin

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 875
Author(s):  
Neha Patel ◽  
Shawn Swavey ◽  
Jayne Robinson
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Opportunistic Pathogen ◽  
Uptake System ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Antibiotic Resistant ◽  
The Matrix ◽  
Life Threatening ◽  
Pre Treatment

One of the greatest threats to human health is the rise in antibiotic-resistant bacterial infections. Pseudomonas aeruginosa (PsA) is an “opportunistic” pathogen known to cause life-threatening infections in immunocompromised individuals and is the most common pathogen in adults with cystic fibrosis (CF). We report here a cationic zinc (II) porphyrin, ZnPor, that effectively kills planktonic and biofilm-associated cells of PsA. In standard tests against 16–18 h-old biofilms, concentrations as low as 16 µg/mL resulted in the extensive disruption and detachment of the matrix. The pre-treatment of biofilms for 30 min with ZnPor at minimum inhibitory concentration (MIC) levels (4 µg/mL) substantially enhanced the ability of tobramycin (Tobra) to kill biofilm-associated cells. We demonstrate the rapid uptake and accumulation of ZnPor in planktonic cells even in dedicated heme-uptake system mutants (ΔPhu, ΔHas, and the double mutant). Furthermore, uptake was unaffected by the ionophore carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Cells pre-exposed to ZnPor took up the cell-impermeant dye SYTOXTM Green in a concentration-dependent manner. The accumulation of ZnPor did not result in cell lysis, nor did the cells develop resistance. Taken together, these properties make ZnPor a promising candidate for treating multi-drug-resistant infections, including persistent, antibiotic-resistant biofilms.

scholarly journals Traditional Chinese Medicine is an Alternative Therapeutic Option for Treatment of Pseudomonas aeruginosa Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
Zheng Pang ◽  
Qingjun Zhu
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Therapeutic Option ◽  
Clinical History ◽  
Opportunistic Pathogen ◽  
Antibiotic Resistant ◽  
Life Threatening ◽  
Conventional Antibiotics

Pseudomonas aeruginosa is an opportunistic pathogen causing life-threatening infections in cystic fibrosis patients and immunocompromised individuals, and it is a leading cause of nosocomial infections associated with significant morbidity and mortality. Treatment of P. aeruginosa infections is challenging due to the antibiotic resistance to most of the conventional antibiotics. Development of alternative therapeutic options is urgently demanded for the patients who have antibiotic-resistant infections. Traditional Chinese medicine (TCM) has a clinical history of thousands of years for prevention and treatment of infectious diseases in China, taking advantages of improving clinical outcomes, producing less side effects, inhibiting pathogen, and modulating host immunity. Recent research has revealed a variety of natural products derived from TCM showing significant antimicrobial effects on antibiotic-resistant strains of P. aeruginosa alone or combined with antibiotics in vitro or in animal models, suggesting that TCM is a promising complementary and alternative therapeutic approach for treatment of chronic P. aeruginosa infections. This review summarizes the recent findings attempting to dissect the mechanisms of TCM combating P. aeruginosa infections and highlights the molecular targets of TCM on P. aeruginosa and host.

scholarly journals Uncovering the molecular mechanisms of the Pseudomonas aeruginosa PA14 response to myxobacterial predation

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Natashia Sydney ◽  
David Whitworth ◽  
Nicholas Tucker
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Molecular Mechanisms ◽  
Opportunistic Pathogen ◽  
World Health Organisation ◽  
Antimicrobial Activities ◽  
World Health ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Susceptibility And Resistance ◽  
Genomic Organisation

Myxobacteria are Gram-negative bacteria, notable for their predatory and antimicrobial activities, which dictate the outcomes of their interactions with neighbouring organisms. They are abundant and widespread in nature, and can significantly affect the microbiome of an environment. We hypothesise that there are underlying molecular mechanisms in prey specieswhich govern the prey’s susceptibility/resistance to the antimicrobial activity of myxobacteria. In this work we attempt to define the mechanisms by which Pseudomonas aeruginosa PA14 resists predation bythe model myxobacterium Myxococcus xanthus. Pseudomonas aeruginosa is an opportunistic pathogen of humans and plants. With the rise in antibiotic resistant organisms, Pseudomonas spp. are categorised as World Health Organisation priority 1 antibiotic-resistant bacteria and are our prey of choice in this study. In collaboration with Dr N. Tucker (Strathclyde), and using a strain of M. xanthus expressing mCherry (courtesy of E. Hoiczyk, Sheffield), we developed 96-well plate assays of predation which measured the optical density of both predator and prey and the florescence of predator at different point intervals. Predation was assayed againsta library of approximately 5700 PA14 mutants to identify strains with increased/decreased susceptibility to predation. Responses of PA14 mutants varied with time and between mutants, allowing us to create a shortlist of candidate genes involved in the prey response to predation. We are currently performing a preliminary analysis of the data using the Integrated Genomic Viewer and Circos plots to assess the genomic organisation of the prey genes that influence susceptibility and resistance to predation.

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