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

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

doi:10.1016/j.bmcl.2003.07.030

Cited by 73 publications

(47 citation statements)

References 10 publications

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“…Given that our overarching goal was to identify therapeutically relevant novel compounds for future medicinal chemistry-based improvement and refinement, we considered that the most desirable compounds would display little or no human cytotoxicity. Indeed, while PA␤N has proven to be a valuable bacterial drug efflux inhibitor tool/compound in the laboratory setting, the compound displays toxicity at concentrations required for antimicrobial efficacy in the host and, consequently, has limited therapeutic promise (34). Thus, to distinguish putatively nontoxic from cytotoxic compounds, conventional 3-(4,5-dimethythiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assays were performed for each compound of interest at 1ϫ and 4ϫ their MEC.…”

Section: Resultsmentioning

confidence: 99%

Identification of Acinetobacter baumannii Serum-Associated Antibiotic Efflux Pump Inhibitors

Blanchard

Barnett

Perlmutter

et al. 2014

Antimicrob Agents Chemother

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Adaptive antibiotic resistance is a newly described phenomenon by which Acinetobacter baumannii induces efflux pump activity in response to host-associated environmental cues that may, in part, account for antibiotic treatment failures against clinically defined susceptible strains. To that end, during adaptation to growth in human serum, the organism induces approximately 22 putative efflux-associated genes and displays efflux-mediated minocycline tolerance at antibiotic concentrations corresponding to patient serum levels. Here, we show that in addition to minocycline, growth in human serum elicits A. baumannii efflux-mediated tolerance to the antibiotics ciprofloxacin, meropenem, tetracycline, and tigecycline. Moreover, using a whole-cell highthroughput screen and secondary assays, we identified novel serum-associated antibiotic efflux inhibitors that potentiated the activities of antibiotics toward serum-grown A. baumannii. Two compounds, Acinetobacter baumannii efflux pump inhibitor 1 ( ABEPI1) [(E)-4-((4-chlorobenzylidene)amino)benezenesulfonamide] and ABEPI2 [N-tert-butyl-2-(1-tert-butyltetrazol-5-yl)sulfanylacetamide], were shown to lead to minocycline accumulation within A. baumannii during serum growth and inhibit the efflux potential of the organism. While both compounds also inhibited the antibiotic efflux properties of the bacterial pathogen Pseudomonas aeruginosa, they did not display significant cytotoxicity toward human cells or mammalian Ca 2؉ channel inhibitory effects, suggesting that ABEPI1 and ABEPI2 represent promising structural scaffolds for the development of new classes of bacterial antibiotic efflux pump inhibitors that can be used to potentiate the activities of current and future antibiotics for the therapeutic intervention of Gram-negative bacterial infections.

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Section: Resultsmentioning

confidence: 99%

Identification of Acinetobacter baumannii Serum-Associated Antibiotic Efflux Pump Inhibitors

Blanchard

Barnett

Perlmutter

et al. 2014

Antimicrob Agents Chemother

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“…Thus, when a wild-type P. aeruginosa strain was plated onto agar with 1 g/ml levofloxacin (8-fold MIC), resistant mutants appeared at a frequency of 10 Ϫ7 ; if 20 g/ml PA␤N was added to the drug, the frequency of appearance of resistant mutants was decreased to only 10 Ϫ11 . Although the PA␤N structure has been modified to decrease acute toxicity to a tolerable level, the presence of two cationic groups led to prolonged accumulation in tissues (presumably in acidic vesicles) and prevented repeated dosing (977). This structural feature was also likely to cause renal toxicity, and thus, the development of this series was abandoned (978).…”

Section: Pa␤nmentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…132 PAbN derivatives are also being explored, an example being MC-04, a compound that displays decreased toxicity, increased stability, and greater activity against P. aeruginosa strains that overexpress efflux pumps, as compared with its parent compound. 133 Other inhibitors such as the aryl-piperazines have also been shown to increase intracellular concentrations of commonly used antibiotics and to reverse MDR phenotypes in a number of ESKAPE pathogens that over-express RND efflux pumps. [134][135][136] However, to date, few EPIs have shown synergy with b-lactam based antibiotics, 137 likely due to the large contribution of other resistance mechanisms such as the b-lactamases.…”

Section: Efflux Pumpsmentioning

confidence: 99%

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

2016

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From humble beginnings of a contaminated petri dish, b-lactam antibiotics have distinguished themselves among some of the most powerful drugs in human history. The devastating effects of antibiotic resistance have nevertheless led to an "arms race" with disquieting prospects. The emergence of multidrug resistant bacteria threatens an ever-dwindling antibiotic arsenal, calling for new discovery, rediscovery, and innovation in b-lactam research. Here the current state of b-lactam antibiotics from a structural perspective was reviewed.

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

Cited by 73 publications

References 10 publications

Identification of Acinetobacter baumannii Serum-Associated Antibiotic Efflux Pump Inhibitors

Identification of Acinetobacter baumannii Serum-Associated Antibiotic Efflux Pump Inhibitors

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

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