Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus

Kumar, Ashwani; Khan, Inshad Ali; Koul, Surrinder; Koul, Jawahir L.; Taneja, Subhash C.; Ali, Intzar; Ali, Furqan; Sharma, Sandeep; Mirza, Zahid Mehmood; Kumar, Manoj; Sangwan, Pyare Lal; Gupta, Pankaj; Thota, Niranjan; Qazi, Ghulam N.

doi:10.1093/jac/dkn088

Cited by 148 publications

(80 citation statements)

References 31 publications

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“…Ampicillin and cefadroxil were chosen as representatives for penicillins and cephalosporins in these assays (see Methods andKumar et al, 2008 andMacLeod et al, 2009 for details). The general patterns observed in the experiments above were duplicated in these assays.…”

Section: Analysis Of Killing Kinetics Indicate That Pbp5 Pbp6 and Damentioning

confidence: 99%

PBP5, PBP6 and DacD play different roles in intrinsic β-lactam resistance of Escherichia coli

et al. 2011

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Escherichia coli PBP5, PBP6 and DacD, encoded by dacA, dacC and dacD, respectively, share substantial amino acid identity and together constitute~50 % of the total penicillin-binding proteins of E. coli. PBP5 helps maintain intrinsic b-lactam resistance within the cell. To test if PBP6 and DacD play simlar roles, we deleted dacC and dacD individually, and dacC in combination with dacA, from E. coli 2443 and compared b-lactam sensitivity of the mutants and the parent strain. b-Lactam resistance was complemented by wild-type, but not DD-carboxypeptidase-deficient PBP5, confirming that enzymic activity of PBP5 is essential for b-lactam resistance. Deletion of dacC and expression of PBP6 during exponential or stationary phase did not alter b-lactam resistance of a dacA mutant. Expression of DacD during mid-exponential phase partially restored b-lactam resistance of the dacA mutant. Therefore, PBP5DD-carboxypeptidase activity is essential for intrinsic b-lactam resistance of E. coli and DacD can partially compensate for PBP5 in this capacity, whereas PBP6 cannot. INTRODUCTIONEscherichia coli encodes 12 penicillin-binding proteins (PBPs), four of which (PBP4, -5, -6 and DacD) have been reported to have DD-carboxypeptidase (DD-CPase) activity (Höltje, 1998; Denome et al., 1999;Ghosh et al., 2008). All these proteins are low molecular mass (LMM) PBPs (Ghuysen, 1991) and are dispensable for survival in vitro (Denome et al., 1999). PBP5 and PBP6 are 62 % identical at the amino acid level and share 48 and 47 % identity with DacD, respectively (Baquero et al., 1996). It has been suggested that these proteins might have similar physiological functions based upon their homology but only PBP5 appears to play a prominent role in maintenance of cell shape (Nelson & Young, 2001;Nelson et al., 2002;Ghosh & Young, 2003). PBP5, PBP6 and DacD are primarily expressed in early exponential, stationary and midexponential phases, respectively (Buchanan & Sowell, 1982;Baquero et al., 1996;Santos et al., 2002), which may explain the different roles of these proteins in maintenance of cell shape. The number of PBP5 molecules is also two-to threefold higher than the number of PBP6 molecules in exponentially growing cells (Spratt, 1977;Dougherty et al., 1996). METHODSBacterial strains and antibiotics. Bacterial strains used in this study were derived from E. coli 2443 and are listed in Table 1. CS18-2K was a gift from Professor Kevin D. Young, University of Arkansas Medical School, AR, USA. The strains were grown in Luria-Bertani (LB) broth, agar (Hi-Media), Muller-Hinton (MH) broth (Hi-Media) and M9-Glucose minimal medium, supplemented with the required amino acids (arginine, proline, leucine and threonine) and thiamine. Chloramphenicol (20 mg ml -1 ), kanamycin (50 mg ml -1 ), tetracycline (25 mg ml -1 ) and ampicillin (50 mg ml -1 ) were added where necessary. Unless otherwise specified, chemicals and reagents were purchased from Sigma. (Table 1). Double and triple mutants were constructed from parents from which the res-npt-res cassette...

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Section: Analysis Of Killing Kinetics Indicate That Pbp5 Pbp6 and Damentioning

confidence: 99%

PBP5, PBP6 and DacD play different roles in intrinsic β-lactam resistance of Escherichia coli

et al. 2011

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“…Several compounds, such as reserpine, behave as if they inhibit efflux pumps and hence have become known as efflux pump inhibitors (EPIs) [4]. Since that time, numerous phytochemicals have been shown to have activity against S. aureus or other Grampositive bacteria, or to act as potential EPIs with antimicrobials for Gram-positive bacteria [5][6][7][8][9][10][11]. Unfortunately, most of the plant-derived compounds have little or no activity with antibiotics against Gram-negative bacteria and it was suggested that, as many plant pathogens are Gram-negative bacteria, plants may not produce molecules effective against these organisms [5].…”

Section: Introductionmentioning

confidence: 99%

Medicinal plant extracts with efflux inhibitory activity against Gram-negative bacteria

Garvey

Rahman

Gibbons

et al. 2011

International Journal of Antimicrobial Agents

115

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“…There are several reports in the literature where natural products have demonstrated enhancement of antimicrobial activity (Khan et al, 2006;Stavri et al, 2007;Werle, 2008;Kumar et al, 2008;Lechner et al, 2008;Sharma et al, 2010). However, the number of natural compounds behaving synergistically with antifungals is minimal.…”

Section: Introductionmentioning

confidence: 99%

In vitro antifungal activities of amphotericin B in combination with acteoside, a phenylethanoid glycoside from Colebrookea oppositifolia

Ali

Sharma

Suri

et al. 2011

Journal of Medical Microbiology

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This study was undertaken to investigate the synergistic interaction between amphotericin B (AmB) and acteoside, isolated from the aerial parts of the shrub Colebrookea oppositifolia (Lamiaceae). Acteoside alone exhibited no intrinsic antifungal activity but showed a potent synergism in combination with AmB against selected pathogenic species, with fractional inhibitory concentration indices in the range of 0.0312-0.1562. The combination of acteoside at 3.12 and 12.5 mg ml -1 with subinhibitory concentrations of AmB resulted in a potent fungicidal effect and also exhibited a significantly extended post-antifungal effect. Furthermore, the combination also reduced the minimum biofilm reduction concentration values of AmB (2-16-fold) in preformed biofilms of Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. There was decreased viability of the cells, increased uptake of propidium iodide and enhanced leakage of 260 nm-absorbing material by Candida albicans cells when exposed to AmB in the presence of acteoside. The reason for potentiation is likely to be that the subinhibitory concentrations of AmB facilitated the uptake of acteoside, which resulted in increased killing of the fungal cells. Administration of acteoside in mice at up to 2000 mg (kg body weight) "1 by the intraperitoneal or oral route produced no overt toxicity. The data presented here support synergism between acteoside and AmB, and it is therefore proposed that a prospective new management strategy for therapeutic application of this combination should be explored.

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Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus

Cited by 148 publications

References 31 publications

PBP5, PBP6 and DacD play different roles in intrinsic β-lactam resistance of Escherichia coli

PBP5, PBP6 and DacD play different roles in intrinsic β-lactam resistance of Escherichia coli

Medicinal plant extracts with efflux inhibitory activity against Gram-negative bacteria

In vitro antifungal activities of amphotericin B in combination with acteoside, a phenylethanoid glycoside from Colebrookea oppositifolia

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