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Effect of phenylalanine arginyl β-naphthylamide on the imipenem resistance, elastase production, and the expression of quorum sensing and virulence factor genes in Pseudomonas aeruginosa clinical isolates

  • Medicine and Public Health - Research Paper
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Abstract

Pseudomonas aeruginosa is one of the most important nosocomial pathogens that possess the ability to produce multiple antibiotic resistance and virulence factors. Elastase B (LasB) is the major factor implicated in tissue invasion and damage during P. aeruginosa infections, whose synthesis is regulated by the quorum sensing (QS) system. Anti-virulence approach is now considered as potential therapeutic alternative and/or adjuvant to current antibiotics’ failure. The aim of this study is primarily to find out the impact of the efflux pump inhibitor (EPI) phenylalanine arginyl β-naphthylamide (PAβN) on the production of elastase B and the gene expression of lasI quorum sensing and lasB virulence factor in clinical isolates of P. aeruginosa. Five P. aeruginosa isolates recovered from patients with respiratory tract infections were examined in this study. Antimicrobial susceptibility of isolates was performed by the disk agar diffusion method. Effect of the PAβN on imipenem susceptibility, bacterial viability, and elastase production was evaluated. The expression of lasB and lasI genes was measured by quantitative real-time PCR in the presence of PAβN. All isolates were identified as multidrug-resistant (MDR) and showed resistance to carbapenem (MIC = 64–256 µg/mL). Susceptibility of isolates to imipenem was highly increased in the presence of efflux inhibitor. PAβN significantly reduced elastase activity in three isolates tested without affecting bacterial growth. In addition, the relative expression of both lasB and lasI genes was diminished in all isolates in the presence of inhibitor. Efflux inhibition by using the EPI PAβN could be a potential target for controlling the P. aeruginosa virulence and pathogenesis. Furthermore, impairment of drug efflux by PAβN indicates its capability to be used as antimicrobial adjuvant that can decrease the resistance and lower the effective doses of current drugs.

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Data availability

The datasets generated and analyzed during this research were included in the main document of this manuscript.

Abbreviations

3-oxo-C12-HSL:

N-(3-oxododecanoyl)-L-homoserine lactone

AHLs:

N-acylhomoserine lactones

ANOVA:

One-way analysis of variance

AMR:

Antimicrobial resistance

BPPL:

Bacterial Priority Pathogens List

C4-HSL:

N-butyryl-L-homoserine lactone

CA-MHB:

Cation-adjusted Mueller–Hinton broth

CFU:

Colony forming unit; CLSI: Clinical Laboratory Standard Institute

CRPA:

Carbapenem-resistant P. aeruginosa

DA-HAI:

Device-associated healthcare-associated infection

ECR:

Elastin Congo red

EPIs:

Efflux pump inhibitors

ICUs:

Intensive care units

INICC:

International Nosocomial Infection Control Consortium

IRPA:

Imipenem-resistant P. aeruginosa

MDCK:

Madin–Darby canine kidney

MDR:

Multidrug-resistant

Mex:

Multidrug efflux pumps

MIC:

Minimum inhibitory concentration

NRT:

No reverse transcriptase

NTC:

No template control

OD:

Optical density

PAβN:

Phenylalanine arginyl β-naphthylamide

PDR:

Pandrug-resistant

QS:

Quorum sensing

rBMD:

reference broth microdilution

RND:

Resistance/nodulation/cell division

RT-qPCR:

Real-time quantitative reverse transcription polymerase chain reaction

TSA:

Tryptic soy agar

TSB:

Tryptic soy broth

WHO:

World Health Organization

XDR:

Extensively drug-resistant

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Acknowledgements

The authors would like to thank all colleagues at the Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran, for their laboratory cooperation.

Funding

The project was financially supported by a grant (Grant No. 111143) from the research deputy of Golestan University of Medical Sciences, Gorgan, Iran.

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Authors and Affiliations

  1. Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran

    Fatemeh Hojjati Zolpirani, Ezat Allah Ghaemi & Abdollah Ardebili

  2. Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

    Fatemeh Hojjati Zolpirani, Ezat Allah Ghaemi & Mohammad Yasaghi

  3. Department of Laboratory Sciences, Langroud School of Allied Medical Sciences, Guilan University of Medical Sciences, Guilan, Iran

    Iraj Nikokar

  4. Medical Bacteriology, Golestan University of Medical Sciences, 49341-74515, Gorgan, Iran

    Abdollah Ardebili

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Contributions

AA and FHZ conceptualized and designed study, performed the experiments, interpreted results, and analyzed data. AA, FHZ, and MY wrote the manuscript and AA critically revised it. EG, IN, and MY helped in setting of the laboratory experiments, interpretation of results, analysis of data, and writing the manuscript. All authors read and approved the final manuscript.

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Correspondence to Abdollah Ardebili.

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Ethics approval and consent to participate

This study was approved by the Ethics Committee of Golestan University of Medical Sciences with ethical code number IR.GOUMS.REC.1399.200. The experiments were performed on previously isolated bacteria from clinical specimens of hospitalized patients. The patients did not directly participate in this research work.

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Zolpirani, F.H., Ghaemi, E.A., Yasaghi, M. et al. Effect of phenylalanine arginyl β-naphthylamide on the imipenem resistance, elastase production, and the expression of quorum sensing and virulence factor genes in Pseudomonas aeruginosa clinical isolates. Braz J Microbiol (2024). https://doi.org/10.1007/s42770-024-01426-7

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