ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSA
Intro: Pseudomonas aeruginosa is an opportunistic pathogen that causes lifethreatening infections. Cefiderocol (CFDC), a new siderophore-cephalosporin, utilizes iron transport systems to penetrate bacterial outer membrane (OM). Resistance can occur due to mutations in these systems reducing drug upt...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-08-01
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| Series: | International Journal of Infectious Diseases |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S120197122300601X |
| _version_ | 1797745241681297408 |
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| author | L. Daoud M.A. Alshamsi S.M. AlNuaimi A.I. Alhammadi M.N. Alfadli A.A. Alali F. Al Marzooq |
| author_facet | L. Daoud M.A. Alshamsi S.M. AlNuaimi A.I. Alhammadi M.N. Alfadli A.A. Alali F. Al Marzooq |
| author_sort | L. Daoud |
| collection | DOAJ |
| description | Intro: Pseudomonas aeruginosa is an opportunistic pathogen that causes lifethreatening infections. Cefiderocol (CFDC), a new siderophore-cephalosporin, utilizes iron transport systems to penetrate bacterial outer membrane (OM). Resistance can occur due to mutations in these systems reducing drug uptake. This study aimed to explore the effect of OM permeabilization on CFDC activity against P. aeruginosa. Methods: Fifty clinical strains of P. aeruginosa were characterized for susceptibility to different antibiotics and screened for beta-lactam resistance genes by PCR. OM permeabilizers (polymyxin B nonapeptide, colistin and EDTA) were tested in combination with CFDC using the checkerboard assay with and without iron. Fluorometric assessment of bacterial OM permeabilization was performed using 1-N-phenylnaphthylamine (NPN) assay. Findings: All the strains were susceptible to CFDC in iron-depleted media with minimum inhibitory concentration (MIC) ≤ 4 µg/ml, although 58% of the strains were multidrug-resistant (MDR) and carbapenem-resistant with detection of VIM (12%) and NDM (10%) carbapenemase genes. The bacteria lost the characteristic green color, and 26% of the strains became non-susceptible to CFDC (MIC: 8-64 µg/ml) in iron-enriched media. Combinations with subinhibitory concentrations of OM permeabilizers were able to significantly lower CFDC MICs in the presence and absence of iron. NPN assay confirmed the damage to OM in the treated bacteria. Discussion: CFDC was potent against MDR P. aeruginosa, with better activity in combination with OM permeabilizers. In iron-enriched condition, loss of bacterial green color indicates less expression of bacterial pigments (pyocyanin and pyoverdine) that act as siderophores to capture iron. If iron acquisition systems are inactive, drug uptake will be reduced explaining higher CFDC MICs in ironenriched conditions. In this case, OM permeabilizers increased drug penetration; thus, reduced CFDC MICs. Conclusion: Outer membrane permeabilization is an effective strategy for enhancing CFDC bactericidal activity on MDR P. aeruginosa. Synergistic combinations can extend the life of existing antibiotics and reduce the potential of antibiotic resistance. |
| first_indexed | 2024-03-12T15:21:32Z |
| format | Article |
| id | doaj.art-27deec7664a043bea0c28ad6e225c508 |
| institution | Directory Open Access Journal |
| issn | 1201-9712 |
| language | English |
| last_indexed | 2024-03-12T15:21:32Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal of Infectious Diseases |
| spelling | doaj.art-27deec7664a043bea0c28ad6e225c5082023-08-11T05:32:17ZengElsevierInternational Journal of Infectious Diseases1201-97122023-08-01134S12ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSAL. Daoud0M.A. Alshamsi1S.M. AlNuaimi2A.I. Alhammadi3M.N. Alfadli4A.A. Alali5F. Al Marzooq6UAE University, Department of Microbiology & Immunology, College of Medicine & Health Sciences, Al Ain, United Arab EmiratesUAE University, Department of Microbiology & Immunology, College of Medicine & Health Sciences, Al Ain, United Arab EmiratesUAE University, Department of Microbiology & Immunology, College of Medicine & Health Sciences, Al Ain, United Arab EmiratesUAE University, Department of Microbiology & Immunology, College of Medicine & Health Sciences, Al Ain, United Arab EmiratesUAE University, Department of Microbiology & Immunology, College of Medicine & Health Sciences, Al Ain, United Arab EmiratesUAE University, Department of Microbiology & Immunology, College of Medicine & Health Sciences, Al Ain, United Arab EmiratesUAE University, Department of Microbiology & Immunology, College of Medicine & Health Sciences, Al Ain, United Arab EmiratesIntro: Pseudomonas aeruginosa is an opportunistic pathogen that causes lifethreatening infections. Cefiderocol (CFDC), a new siderophore-cephalosporin, utilizes iron transport systems to penetrate bacterial outer membrane (OM). Resistance can occur due to mutations in these systems reducing drug uptake. This study aimed to explore the effect of OM permeabilization on CFDC activity against P. aeruginosa. Methods: Fifty clinical strains of P. aeruginosa were characterized for susceptibility to different antibiotics and screened for beta-lactam resistance genes by PCR. OM permeabilizers (polymyxin B nonapeptide, colistin and EDTA) were tested in combination with CFDC using the checkerboard assay with and without iron. Fluorometric assessment of bacterial OM permeabilization was performed using 1-N-phenylnaphthylamine (NPN) assay. Findings: All the strains were susceptible to CFDC in iron-depleted media with minimum inhibitory concentration (MIC) ≤ 4 µg/ml, although 58% of the strains were multidrug-resistant (MDR) and carbapenem-resistant with detection of VIM (12%) and NDM (10%) carbapenemase genes. The bacteria lost the characteristic green color, and 26% of the strains became non-susceptible to CFDC (MIC: 8-64 µg/ml) in iron-enriched media. Combinations with subinhibitory concentrations of OM permeabilizers were able to significantly lower CFDC MICs in the presence and absence of iron. NPN assay confirmed the damage to OM in the treated bacteria. Discussion: CFDC was potent against MDR P. aeruginosa, with better activity in combination with OM permeabilizers. In iron-enriched condition, loss of bacterial green color indicates less expression of bacterial pigments (pyocyanin and pyoverdine) that act as siderophores to capture iron. If iron acquisition systems are inactive, drug uptake will be reduced explaining higher CFDC MICs in ironenriched conditions. In this case, OM permeabilizers increased drug penetration; thus, reduced CFDC MICs. Conclusion: Outer membrane permeabilization is an effective strategy for enhancing CFDC bactericidal activity on MDR P. aeruginosa. Synergistic combinations can extend the life of existing antibiotics and reduce the potential of antibiotic resistance.http://www.sciencedirect.com/science/article/pii/S120197122300601X |
| spellingShingle | L. Daoud M.A. Alshamsi S.M. AlNuaimi A.I. Alhammadi M.N. Alfadli A.A. Alali F. Al Marzooq ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSA International Journal of Infectious Diseases |
| title | ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSA |
| title_full | ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSA |
| title_fullStr | ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSA |
| title_full_unstemmed | ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSA |
| title_short | ASSESSING THE EFFECT OF OUTER MEMBRANE PERMEABILIZATION FOR POTENTIATING THE ANTIBACTERIAL ACTIVITY OF CEFIDEROCOL ON PSEUDOMONAS AERUGINOSA |
| title_sort | assessing the effect of outer membrane permeabilization for potentiating the antibacterial activity of cefiderocol on pseudomonas aeruginosa |
| url | http://www.sciencedirect.com/science/article/pii/S120197122300601X |
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