Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa

Nosocomial infections by Pseudomonas aeruginosa continue to be a widespread problem in Asia, North and South America, and Europe. Carbapenems are the most potent β-lactams against P. aeruginosa because its strong affinity to penicillin binding proteins, stability against most serine β-lactamases and high permeability across the outer membrane (7,8). However, intensive use of the carbapenems facilitated the emergence of carbapenem-resistant P. aeruginosa. Low level resistance to imipenem (MIC, 8 to 32 µg/ml) in P. aeruginosa is mostly due to reduced uptake of the drug as a result of loss of the porin OprD (8). This mechanism correlates with continued expression of AmpC β-lactamase. Resistance to meropenem but not imipenem may also arise via overexpression of the MexA-MexBOprM efflux pump (14). High level resistance to carbapenems (MICϾ32 µg/ml) can be caused by the presence of metallo-β-lactamase, which exhibits a broadspectrum resistance to β-lactams including carbapenems. Metallo-β-lactamase-producing P. aeruginosa Abstract: Pseudomonas aeruginosa showing resistance to imipenem were found in 100 of 1,058 strains (9.5%) from six hospitals (a-f) in Hiroshima City, Japan. Of the 100 strains, 14 (14%) were double disk synergy test positive using sodium mercaptoacetic acid disks, and 18 (18%) were bla IMP-1 or blaVIM-2 allele positive by polymerase chain reaction (PCR). Among 100 imipenem-resistant strains, 32 were categorized into multi-drug resistant strains, in which 13 were positive for the metallo-␤-lactamase gene. Fifty-one strains (51%) among the 100 imipenem-resistant strains had elevated RND efflux pump activity against levofloxacin. But only 6 of 51 strains were classified as multi-drug resistant strains. The pulsed field gel electrophoresis analysis of the SpeI-digested DNA from the 100 isolates suggested not only clonal spread but spread of heterogeneous clones started to contribute to the prevalence of metallo-␤-lactamase producing P. aeruginosa strains in Japanese hospitals.

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“…The contribution of the efflux pump was judged significant if the inhibitor decreased the MIC of levofloxacin eightfold or greater (17,19).…”

Section: Methodsmentioning

confidence: 99%

Molecular Characterization of Imipenem‐Resistant Pseudomonas aeruginosa in Hiroshima, Japan

Ohara

Kouda

Onodera

et al. 2007

Microbiology and Immunology

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“…For example, corilagin, 8,9) tellimagrandin I, 9,10) epicatechin gallate, 11) epigallocatechin gallate 12) or many flavonoids 13) potentiated antibacterial activity of b-lactams against methicillin-resistant Staphylococcus aureus (MRSA). Baicalein potentiated activities of tetracycline and b-lactams against MRSA, 14) 5Ј-methoxyhydonocarpin inhibited NorA pump in S. aureus 15) and MC-207,110 (phenylalanine arginine bnaphthylamide, PAbN) and its relatives potentiated some types of antimicrobials that are substrates of one of multidrug efflux pumps, MexAB-OprM of Pseudomonas aeruginosa [16][17][18][19][20][21] or AcrAB-TolC of Escherichia coli 22) and Enterobacter aerogenes. 23) Regarding to VRE, allicin, which potentiated activity of vancomycin against VRE, 24) and [10]gingerol and some detergents, such as sodium dodecyl sulfate (SDS) and Triton X-100, which potentiated some antimicrobials including aminoglycosides against enterococci 25) have been reported.…”

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confidence: 99%

Potentiation of Antimicrobial Activity of Aminoglycosides by Carnosol from Salvia officinalis

Horiuchi

Shiota

Kuroda

et al. 2007

Biological & Pharmaceutical Bulletin

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We found that a crude extract from Salvia officinalis (sage) reduced the minimum inhibitory concentrations (MICs) of aminoglycosides in vancomycin-resistant enterococci (VRE). We isolated the effective compound from the extract and identified it as carnosol, one of diterpenoids. Carnosol showed a weak antimicrobial activity, and greatly reduced the MICs of various aminoglycosides (potentiated the antimicrobial activity of aminoglycosides) and some other types of antimicrobial agents in VRE. Carnosic acid, a related compound, showed the similar activity. The effect of carnosol and carnosic acid with gentamicin was synergistic.

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“…Despite the potential of this combinatorial regimen in APDT, no clinical feasibility studies have yet been performed, mainly due to the biological instability, poor solubility, and in vivo toxicity of some export pump inhibitors [201]. These factors, however, do not rule out the utility of this approach for the treatment of local infections, such as those that cause dental diseases and in superficial skin wounds, where systemic toxicity issues can be avoided.…”

Section: Efflux Pump Inhibitorsmentioning

confidence: 99%

Antibacterial photodynamic therapy: overview of a promising approach to fight antibiotic-resistant bacterial infections

et al. 2015

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Antibacterial photodynamic therapy (APDT) has drawn increasing attention from the scientific society for its potential to effectively kill multidrug-resistant pathogenic bacteria and for its low tendency to induce drug resistance that bacteria can rapidly develop against traditional antibiotic therapy. The review summarizes the mechanism of action of APDT, the photosensitizers, the barriers to PS localization, the targets, the in vitro-, in vivo-, and clinical evidence, the current developments in terms of treating Gram-positive and Gram-negative bacteria, the limitations, as well as future perspectives. Relevance for patients: A structured overview of all important aspects of APDT is provided in the context of resistant bacterial species. The information presented is relevant and accessible for scientists as well as clinicians, whose joint effort is required to ensure that this technology benefits patients in the post-antibiotic era.

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Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa

Cited by 92 publications

References 7 publications

Molecular Characterization of Imipenem‐Resistant Pseudomonas aeruginosa in Hiroshima, Japan

Molecular Characterization of Imipenem‐Resistant Pseudomonas aeruginosa in Hiroshima, Japan

Potentiation of Antimicrobial Activity of Aminoglycosides by Carnosol from Salvia officinalis

Antibacterial photodynamic therapy: overview of a promising approach to fight antibiotic-resistant bacterial infections

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