Auranofin inhibits virulence in Pseudomonas aeruginosa

AbstractPseudomonas aeruginosa is widely attributed as the leading cause of hospital-acquired infections. Due to intrinsic antibiotic resistance mechanisms and the ability to form biofilms, P. aeruginosa infections are challenging to treat. P. aeruginosa employs multiple virulence mechanisms to establish infections, many of which are controlled by the global virulence regulator Vfr. An attractive strategy to combat P. aeruginosa infections is thus the use of anti-virulence compounds. Here, we report the discovery that FDA-approved drug auranofin attenuates virulence in P. aeruginosa. We demonstrate that auranofin acts by targeting Vfr, which in turn leads to inhibition of quorum sensing (QS) and Type IV pili (TFP). Consistent with inhibition of QS and TFP expression, we show that auranofin attenuates biofilm maturation, and when used in combination with colistin, displays strong synergy in eradicating P. aeruginosa biofilms. Auranofin may have immediate applications as an anti-virulence drug against P. aeruginosa infections.

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Role of Pseudomonas aeruginosa AmpR on β-lactam and non-β-lactam transient cross-resistance upon pre-exposure to subinhibitory concentrations of antibiotics

Journal of Medical Microbiology ◽

10.1099/jmm.0.070185-0 ◽

2014 ◽

Vol 63 (4) ◽

pp. 544-555 ◽

Cited By ~ 26

Author(s):

Hansi Kumari ◽

Deepak Balasubramanian ◽

Diansy Zincke ◽

Kalai Mathee

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Efflux Pump ◽

Chronically Ill ◽

Cross Resistance ◽

Elevated Expression ◽

Subinhibitory Concentrations ◽

Hospital Acquired ◽

Virulence Regulator

Pseudomonas aeruginosa is one of the most dreaded opportunistic pathogens accounting for 10 % of hospital-acquired infections, with a 50 % mortality rate in chronically ill patients. The increased prevalence of drug-resistant isolates is a major cause of concern. Resistance in P. aeruginosa is mediated by various mechanisms, some of which are shared among different classes of antibiotics and which raise the possibility of cross-resistance. The goal of this study was to explore the effect of subinhibitory concentrations (SICs) of clinically relevant antibiotics and the role of a global antibiotic resistance and virulence regulator, AmpR, in developing cross-resistance. We investigated the induction of transient cross-resistance in P. aeruginosa PAO1 upon exposure to SICs of antibiotics. Pre-exposure to carbapenems, specifically imipenem, even at 3 ng ml−1, adversely affected the efficacy of clinically used penicillins and cephalosporins. The high β-lactam resistance was due to elevated expression of both ampC and ampR, encoding a chromosomal β-lactamase and its regulator, respectively. Differences in the susceptibility of ampR and ampC mutants suggested non-AmpC-mediated regulation of β-lactam resistance by AmpR. The increased susceptibility of P. aeruginosa in the absence of ampR to various antibiotics upon SIC exposure suggests that AmpR plays a major role in the cross-resistance. AmpR was shown previously to be involved in resistance to quinolones by regulating MexEF–OprN efflux pump. The data here further indicate the role of AmpR in cross-resistance between quinolones and aminoglycosides. This was confirmed using quantitative PCR, where expression of the mexEF efflux pump was further induced by ciprofloxacin and tobramycin, its substrate and a non-substrate, respectively, in the absence of ampR. The data presented here highlight the intricate cross-regulation of antibiotic resistance pathways at SICs of antibiotics and the need for careful assessment of the order of antibiotic regimens as this may have dire consequences. Targeting a global regulator such as AmpR that connects diverse pathways is a feasible therapeutic approach to combat P. aeruginosa pathogenesis.

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Inactivation of Nitrite-Dependent Nitric Oxide Biosynthesis Is Responsible for Overlapped Antibiotic Resistance between Naturally and Artificially Evolved Pseudomonas aeruginosa

mSystems ◽

10.1128/msystems.00732-21 ◽

2021 ◽

Author(s):

Su-fang Kuang ◽

Ding-yun Feng ◽

Zhuang-gui Chen ◽

Zhuo-zheng Liang ◽

Juan-juan Xiang ◽

...

Keyword(s):

Nitric Oxide ◽

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Content Type ◽

Hospital Acquired Infections ◽

Hospital Acquired

Infections with Pseudomonas aeruginosa have become a real concern among hospital-acquired infections, especially in cystic fibrosis patients and immunocompromised individuals. Control of the pathogen is challenging due to antibiotic resistance.

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Phenotypic and Genotypic Determination of Resistance to Common Disinfectants Among Strains of Pseudomonas Aeruginosa Producing and Non-Producing Biofilm Isolated From Iran

10.21203/rs.3.rs-918248/v1 ◽

2021 ◽

Author(s):

Mehdi Bakht ◽

Safar Ali Alizadeh ◽

Sara Rahimi ◽

Raana Kazemzade anari ◽

Mohammad Rostamani ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Acetic Acid ◽

Sodium Hypochlorite ◽

Efflux Pump ◽

Antimicrobial Susceptibility Test ◽

Present Survey ◽

Hospital Acquired Infections ◽

Hospital Acquired

Abstract Background: One of the most important reasons for human mortality worldwide is Hospital-acquired infections, which can be controlled by efficient use of proper disinfectants for the Hospital settings. The main aim of the present survey was to assess the susceptibility of Pseudomonas aeruginosa producing and non-producing biofilm isolated to the five commonly used Hospital disinfectants, and evaluation of the synergistic effect of selective disinfectants and Ethylene-diamine-tetra acetic acid (EDTA), and the effect of exposure to sub-inhibitory concentrations of Sodium hypochlorite on antimicrobial susceptibility test.Results: The results showed that Sodium hypochlorite 5%, and Ethanol 70% is the most and less potent disinfectants against Pseudomonas aeruginosa, respectively. Clearly, the addition of EDTA increased the efficacy of selected disinfectants significantly. The changes in the antibiotic-resistance profiles after exposure to sub-inhibitory concentrations of disinfectants were observed for different classes of antibiotics. As well as near the all isolates harbored efflux pump genes and produced biofilm. Conclusion: For disinfection of Hospital surfaces and instruments, the mixture of disinfectant and EDTA were the most suitable selection in this study. In our study, it was clear that exposure to sub-inhibitory concentrations of disinfectants results in resistance to antibiotics. Also, strong and intermediate biofilm formers belonged to MDR/XDR strains.

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Pseudomonas aeruginosa: Diseases, Biofilm and Antibiotic Resistance

10.5772/intechopen.95251 ◽

2020 ◽

Author(s):

Hussein Al-Dahmoshi ◽

Raad D. Al-Obaidi ◽

Noor Al-Khafaji

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Blood Stream Infection ◽

Surgical Site Infections ◽

Blood Stream ◽

Central Line ◽

Resistance Mechanisms ◽

Resistance Patterns ◽

Tract Infections ◽

Hospital Acquired

Pseudomonas aeruginosa is Gram negative bacteria that can adapt to extreme environmental conditions and withstand to different antibacterial agents. It si responsible for arrays of infections both community and hospital acquired especially ICU infections. Respiratory tract infection, blood stream infection, wound infection, burn infection, and urinary tract infections ware top five P. aeruginosa infections. Additionally as an opportunistic bacteria, it may be associated with healthcare infections in intensive care units (ICUs), ventilator-associated pneumonia (VAP), central line-associated blood stream infections, surgical site infections, otitis media, and keratitis. P. aeruginosa can form biofilms as self-produced extracellular matrix to protects the cells from antibiotics and the host immune response. Antibiotic resistance was an prominent feature of this pathogen and can donate it one of the three resistance patterns: Multidrug (MDR), extensive drug (XDR) and pan drug resistance. It exploit many resistance mechanisms ranged from overexpression of drug efflux systems protein, modifying enzyme production, reducing the permeability and using shelters like biofilms.

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Faculty Opinions recommendation of Biofilm formation by Pseudomonas aeruginosa wild type, flagella and type IV pili mutants.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1011135.192160 ◽

2003 ◽

Author(s):

Leo Eberl

Keyword(s):

Pseudomonas Aeruginosa ◽

Biofilm Formation ◽

Type Iv Pili ◽

Wild Type ◽

Type Iv

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Faculty Opinions recommendation of Distinct function of Pseudomonas aeruginosa type IV pili disclosed in the bacterial pass-through of membrane filter with smaller pore sizes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1081001.533960 ◽

2007 ◽

Author(s):

Esther Bullitt

Keyword(s):

Pseudomonas Aeruginosa ◽

Membrane Filter ◽

Type Iv Pili ◽

Pore Sizes ◽

Type Iv ◽

Pass Through

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Assessing the Molecular Targets and Mode of Action of Furanone C-30 on Pseudomonas aeruginosa Quorum Sensing

Molecules ◽

10.3390/molecules26061620 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1620

Author(s):

Victor Markus ◽

Karina Golberg ◽

Kerem Teralı ◽

Nazmi Ozer ◽

Esti Kramarsky-Winter ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Quorum Sensing ◽

Conformational Changes ◽

Mode Of Action ◽

Pathogenic Bacteria ◽

Molecular Targets ◽

Resistant Bacteria ◽

Public Healthcare ◽

C 30

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein’s productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date.

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Aztreonam Lysine Increases the Activity of Phages E79 and phiKZ against Pseudomonas aeruginosa PA01

Microorganisms ◽

10.3390/microorganisms9010152 ◽

2021 ◽

Vol 9 (1) ◽

pp. 152

Author(s):

Carly M. Davis ◽

Jaclyn G. McCutcheon ◽

Jonathan J. Dennis

Keyword(s):

Pseudomonas Aeruginosa ◽

Morphological Changes ◽

Burst Size ◽

Type Iv Pili ◽

Biofilm Growth ◽

Promising Alternative ◽

Type Iv ◽

Alternative Treatment Option ◽

One Step ◽

Step Growth

Pseudomonas aeruginosa is a pernicious bacterial pathogen that is difficult to treat because of high levels of antibiotic resistance. A promising alternative treatment option for such bacteria is the application of bacteriophages; the correct combination of phages plus antibiotics can produce synergistic inhibitory effects. In this study, we describe morphological changes induced by sub-MIC levels of the antibiotic aztreonam lysine (AzLys) on P. aeruginosa PA01, which may in part explain the observed phage–antibiotic synergy (PAS). One-step growth curves for phage E79 showed increased adsorption rates, decreased infection latency, accelerated time to lysis and a minor reduction in burst size. Phage E79 plus AzLys PAS was also able to significantly reduce P. aeruginosa biofilm growth over 3-fold as compared to phage treatment alone. Sub-inhibitory AzLys-induced filamentation of P. aeruginosa cells resulted in loss of twitching motility and a reduction in swimming motility, likely due to a reduction in the number of polar Type IV pili and flagella, respectively, on the filamented cell surfaces. Phage phiKZ, which uses Type IV pili as a receptor, did not exhibit increased activity with AzLys at lower sub-inhibitory levels, but still produced phage–antibiotic synergistic killing with sub-inhibitory AzLys. A one-step growth curve indicates that phiKZ in the presence of AzLys also exhibits a decreased infection latency and moderately undergoes accelerated time to lysis. In contrast to prior PAS studies demonstrating that phages undergo delayed time to lysis with cell filamentation, these PAS results show that phages undergo accelerated time to lysis, which therefore suggests that PAS is dependent upon multiple factors, including the type of phages and antibiotics used, and the bacterial host being tested.

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