The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus

Schmitz, Franz‐Josef; Fluit, Ad C.; Lückefahr, Marc; Engler, Beate; Hofmann, B.; Verhoef, J.; Heinz, Hans‐Peter; Hadding, U.; Jones, Mark

doi:10.1093/jac/42.6.807

Cited by 142 publications

(140 citation statements)

References 9 publications

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“…Also, additive effects were observed with RES and these antibiotics against other strains. This fact supports in general previous studies (Gibbons and Udo, 2000;Gibbons et al, 2003;Schmitz et al, 1998). However, only a 2-fold reduction of MIC was observed between RES and CIP against SA1199B.…”

Section: Discussionsupporting

confidence: 92%

“…Concerning strains SA1199B, XU212, and RN4220, potentiation was obtained between CIP-QUIN, TET-RES, and ERY-PYR, respectively. RES, originally extracted from Rauwolfia serpentina, was already studied by several authors due to its properties as EPI (Aeschlimann et al, 1999;Gibbons and Udo, 2000;Markham et al, 1999;Schmitz et al, 1998). In this work, this alkaloid showed a potentiating activity when combined with TET against XU212 and MSSA10 and with CIP against MRSA2.…”

Section: Discussionmentioning

confidence: 61%

“…While RES had effect on some S. aureus strains, for others, no effect was observed. This can be associated to the fact that strains could vary in the extent to which RES is able to block NorA or TetK or, also, due to the varying rates of transcription of the nor and tetK genes or differences in the stability of its messenger RNA (Schmitz et al, 1998). RES was applied at concentrations lower than its IC50, which shows that RES can be a good candidate to be used as cotherapeutic agent.…”

Section: Discussionmentioning

confidence: 99%

“…Also, several antibiotic adjuvants have been evaluated for their action as resistance-modifying agents (RMAs) (Hemaiswarya et al, 2008), i.e., compounds that can modify or inhibit the bacterial mechanisms of resistance, so that antibiotics can efficiently kill the resistant bacteria. Several RMAs were already described (Chan et al, 2011;Gibbons et al, 2003;Khan et al, 2006;Roccaro et al, 2004;Schmitz et al, 1998;Yam et al, 1998). Efflux pump inhibitors (EPIs) are important examples of RMAs since they can prevent the extrusion of an antibiotic to the exterior of the cell and thus allow the antibiotic to act efficiently against bacteria.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the best method to assess antibiotic potentiation by phytochemicals against Staphylococcus aureus

Abreu

Serra

Borges

et al. 2014

Diagnostic Microbiology and Infectious Disease

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The increasing occurrence of bacterial resistance to antibiotics has now reached a critical level. Finding antibiotic coadjuvants capable to inhibit the bacterial resistance mechanisms would be a valuable mid-term solution, until new classes of antibiotics are discovered. Selected plant alkaloids were combined with 5 antibiotics against 10 Staphylococcus aureus strains, including strains expressing distinct efflux pumps and methicillin-resistant S. aureus strains. The efficacy of each combination was assessed using the microdilution checkerboard, time-kill, Etest, and disc diffusion methods. The cytotoxicity of the alkaloids was evaluated in a mouse fibroblast cell line. Potentiation was obtained in 6% of all 190 combinations, especially with the combination of: ciprofloxacin with reserpine (RES), pyrrolidine (PYR), and quinine (QUIN); tetracycline with RES; and erythromycin with PYR. The highest cytotoxicity values were found for QUIN (half maximal inhibitory concentration [IC50] = 25 ± 2.2 mg/L) and theophylline (IC50 = 100 ± 4.7 mg/L).

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of the best method to assess antibiotic potentiation by phytochemicals against Staphylococcus aureus

Abreu

Serra

Borges

et al. 2014

Diagnostic Microbiology and Infectious Disease

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“…This plant alkaloid has been described to function as an EPI in various Gram-positive pathogens, such as Staphylococcus aureus (13,17) and Streptococcus pneumoniae (18), aiding in the restoration of antibiotic susceptibility among MDR strains of these clinically prevalent bacteria. Our data suggest that reserpine potentiates MB-1 activity, in vitro and in vivo, although the exact mechanism(s) behind this potentiation is still unclear.…”

mentioning

confidence: 99%

Potentiation of Antibacterial Activity of the MB-1 Siderophore-Monobactam Conjugate Using an Efflux Pump Inhibitor

Tomaras

Crandon

McPherson

et al. 2015

Antimicrob Agents Chemother

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Preliminary enthusiasm over the encouraging spectrum and in vitro activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivo efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosa and provide evidence that efflux inhibition may circumvent this in vivo-relevant resistance liability.T he extent and severity of antibiotic resistance in Gram-negative pathogens require the development of innovative therapeutic interventions that not only circumvent existing clinically relevant resistance mechanisms but will also result in limited spontaneous resistance emergence. Although standard in vitro methodologies exist for predicting resistance development, translational deficiencies that can stem from their lack of in vivo physiological relevance are becoming increasingly apparent. We previously described the siderophore-monobactam conjugate MB-1 ( Fig. 1 [1]), which has broad-spectrum in vitro activities against multidrug-resistant (MDR) Gram-negative pathogens, including Pseudomonas aeruginosa, when tested using standard methods established by the Clinical and Laboratory Standards Institute (CLSI) (1). Unfortunately, we have also demonstrated that despite these encouraging in vitro activities, the efficacy of MB-1 in a neutropenic murine infection model was highly variable and not directly predictable from traditional in vitro activity assays (2). Instead, the development of a modified in vitro resistance frequency assay, which relies on the utilization of more in vivo-relevant iron conditions, has proven to be more predictive of the efficacy of MB-1 in vivo. Additionally, this assay has demonstrated a role for endogenous siderophores, such as pyoverdine, in mediating the adaptive cellular response that enables P. aeruginosa to transiently resist MB-1 activity (2). While these results suggest that the use of MB-1 as monotherapy is not a viable option, we have speculated about alternative strategies that may mitigate this adaptive response and resurrect MB-1 as a legitimate antibacterial agent. Among these potentiation-type approaches, we considered the idea that inhibiting endogenous siderophore functionality should circumvent the adaptation phenotype mediated by the competition for iron by native siderophore systems. Siderophore secretion into the extracellular milieu has been shown to be dependent on functional efflux pumps in Gram-negative bacteria (3-5). In the case of P. aeruginosa, the secretion of newly synthesized pyoverdine is accomplished by the ABC transporter-type efflux system encoded by pvdR, pvdT, and opmQ (6). Additionally, this system is responsible for pyoverdine recycling after successive rounds of iron acquisition and delivery (7).To prove that inhibiting the activity of this pump can potentiate the activity of MB-1, we generated a pvdRT-op...

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3‐Aryl‐4‐methyl‐2‐quinolones Targeting Multiresistant Staphylococcus aureus Bacteria

Doléans-Jordheim¹,

Véron²,

Fendrich³

et al. 2013

ChemMedChem

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The NorA efflux pump lowers intracellular fluoroquinolone concentrations by expelling antibiotics through the membrane of Staphylococcus aureus. We identified 3-aryl-4-methyl-2-quinolin-2-ones as compounds able to restore the activity of the NorA substrate, ciprofloxacin, against resistant S. aureus strains, and acting as efflux pump inhibitors (EPI). In particular, 5-hydroxy-7-methoxy-4-methyl-3-phenylquinolin-2-one (6 c) presents both an EPI and an antimicrobial effect. Its efficacy and safety make it a potential candidate for further investigations.

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The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus

Cited by 142 publications

References 9 publications

Evaluation of the best method to assess antibiotic potentiation by phytochemicals against Staphylococcus aureus

Evaluation of the best method to assess antibiotic potentiation by phytochemicals against Staphylococcus aureus

Potentiation of Antibacterial Activity of the MB-1 Siderophore-Monobactam Conjugate Using an Efflux Pump Inhibitor

3‐Aryl‐4‐methyl‐2‐quinolones Targeting Multiresistant Staphylococcus aureus Bacteria

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