Use of an Efflux Pump Inhibitor To Determine the Prevalence of Efflux Pump-Mediated Fluoroquinolone Resistance and Multidrug Resistance in Pseudomonas aeruginosa

Q2 · MEDICINE

Article

Author: Kriengkauykiat, Jane ; Porter, Edith ; Wong-Beringer, Annie ; Lomovskaya, Olga

ABSTRACT Fluoroquinolone-resistance in Pseudomonas aeruginosa may be due to efflux pump overexpression (EPO) and/or target mutations. EPO can result in multidrug resistance (MDR) due to broad substrate specificity of the pumps. MC-04,124, an efflux pump inhibitor (EPI) shown to significantly potentiate activity of levofloxacin in P. aeruginosa , was used to examine the prevalence of EPO in clinical isolates. MICs were determined for ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin with or without EPI and for other antipseudomonal agents by using broth microdilution against P. aeruginosa isolates from adults ( n = 119) and children ( n = 24). The prevalence of the EPO phenotype (≥8-fold MIC decrease when tested with EPI) was compared among subgroups with different resistance profiles. The EPO phenotype was more prevalent among levofloxacin-resistant than levofloxacin-sensitive strains (61%, 48/79 versus 9%, 6/64). EPO was present in 60% of fluoroquinolone-resistant strains without cross-resistance, while it was present at variable frequencies among strains with cross-resistance to other agents: piperacillin-tazobactam (86%), ceftazidime (76%), cefepime (65%), imipenem (56%), gentamicin (55%), tobramycin (48%), and amikacin (27%). The magnitude of MIC decrease with an EPI paralleled the frequency of which the EPO phenotype was observed in different subgroups. EPI reduced the levofloxacin MIC by as much as 16-fold in eight strains for which MICs were 128 μg/ml. Efflux-mediated resistance appears to contribute significantly to fluoroquinolone resistance and MDR in P. aeruginosa . Our data support the fact that increased fluoroquinolone usage can negatively impact susceptibility of P. aeruginosa to multiple classes of antipseudomonal agents.

01 Dec 2003·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

The relationship between physicochemical properties, In vitro activity and pharmacokinetic profiles of analogues of diamine-Containing efflux pump inhibitors

Q4 · MEDICINE

Article

Author: Thomas E. Renau ; David Griffith ; Nicole Williams ; Michael N. Dudley ; Yakira Landaverry ; William J. Watkins ; Keith Huie ; Vrushali Tembe ; Roger Léger ; Jason Z. Zhang ; Rose Yen ; Renée Litman ; Suzanne Chamberland ; Deidre Madsen

Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.

Journal of Antimicrobial ChemotherapyQ2 · MEDICINE

Effect of efflux pump inhibitors on bile resistance and in vivo colonization of Campylobacter jejuni

Q2 · MEDICINE

Article

Author: Ad'Lynn Martinez ; Jun Lin

OBJECTIVESThe multidrug efflux pump CmeABC is essential for Campylobacter colonization in animal intestine by mediating bile resistance. The objective of this study is to examine the effect of inhibition of the CmeABC pump by efflux pump inhibitor (EPI) on the susceptibility of Campylobacter to bile salts and to evaluate the in vivo efficacy of two EPIs on the colonization of Campylobacter in a host.METHODSTwo wild-type Campylobacter jejuni strains and their isogenic cmeB mutants were used to determine the susceptibilities of the strains to various bile salts in the presence of EPI MC-207,110 or MC-04,124. The in vivo effect of the EPIs on the colonization of C. jejuni in a host was evaluated using a chicken model system.RESULTSThe presence of EPIs resulted in a 16- to 512-fold reduction in the MICs of bile salts in both C. jejuni strains. Compared with wild-type strains, cmeB mutants displayed much smaller magnitudes of reduction in the MICs of bile salts, indicating that the in vitro effect of the EPI is primarily mediated by the CmeABC efflux pump. Investigation of 21 Campylobacter isolates from various origins further showed that the EPI MC-207,110 decreased bile resistance in all isolates. Single oral administration of EPI (MC-207,110 or MC-04,124) at two different doses reduced colonization of C. jejuni in chickens at 2-4 days post-inoculation only. Oral administration of MC-207,110 for three consecutive days following inoculation of C. jejuni did not result in a more significant reduction in the level of Campylobacter colonization in chickens.CONCLUSIONSInhibition of Campylobacter efflux pumps by EPIs is a potential means for therapeutic intervention to reduce colonization of C. jejuni in humans and animal reservoirs.

100 Deals associated with MC-04124

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Gram-Negative Bacterial Infections	Phase 2	US	Essential Therapeutics, Inc.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

MC-04124

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation