Quinazolinone fungal efflux pump inhibitors. Part 3: (N-methyl)piperazine variants and pharmacokinetic optimization

Watkins, William J.; Chong, Lee S.; Cho, Aesop; Hilgenkamp, Ramona; Ludwikow, M.; Garizi, Negar; Iqbal, Nadeem; Barnard, John; Singh, Rajeshwar; Madsen, D. E.; Lolans, Karen; Lomovskaya, Olga; Oza, Uma; Kumaraswamy, Padmapriya; Blecken, Andrea; Bai, Shuang; Loury, Dana N.; Griffith, David C.; Dudley, Michael N.

doi:10.1016/j.bmcl.2007.02.047

Cited by 22 publications

(9 citation statements)

References 7 publications

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“…Several classes of EPIs have been reported in the literature and are being pursued in drug development programs. 112–116 Phenylalanyl-arginyl- β -naphthylamide and analogous arylamines are broad-spectrum EPIs with activities against Gram-negative bacteria; 113,117,118 arylpiperidines 119 and more recently pyrinopyridine 120 are inhibitors of AcrAB-TolC from E. coli . Likewise, pyridopyrimidines are specific inhibitors of P. aeruginosa MexB and E. coli AcrB.…”

Section: Approaches To Bypass or Break The Permeability Barriermentioning

confidence: 99%

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

2015

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Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections that are effectively untreatable present a serious threat to public health. The problem is broadly recognized and tackled at both the fundamental and applied levels. This paper summarizes current advances in understanding the molecular bases of the low permeability barrier of Gram-negative pathogens, which is the major obstacle in discovery and development of antibiotics effective against such pathogens. Gaps in knowledge and specific strategies to break this barrier and to achieve potent activities against difficult Gram-negative bacteria are also discussed.

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Section: Approaches To Bypass or Break The Permeability Barriermentioning

confidence: 99%

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

2015

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“…Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with improved physical properties and activity against clinically-relevant Candida spp. [144]. The list of fungal EPIs is further expanded with the cyclic peptides unnarmicin A and unnarmicin C that were identified by testing a library of marine microorganisms [145] sulfated sterols from the marine sponge Topsentia sp [146], acridone derivatives [147] and ibuprofen [148].…”

Section: Fungal Epismentioning

confidence: 99%

Microbial Efflux Pump Inhibition: Tactics and Strategies

Tegos

Haynes²,

Strouse³

et al. 2011

CPD

132

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Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs.

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“…To reverse fungal FLC resistance, a putative chemosensitizer should be nontoxic in the absence of FLC but render a normally FLC-resistant strain more sensitive to FLC. Inhibitors of fungal ABC transporters include FK506 (30,42), enniatin (13), milbemycins (20), unnarmicins (48), isonitrile (56), disulfiram (44), ibuprofen (36), and quinazolinone derivatives (51). Such inhibitors, or chemosensitizers, may act indirectly on aspects of metabolism that affect efflux.…”

mentioning

confidence: 99%

ABC Transporter Cdr1p Contributes More than Cdr2p Does to Fluconazole Efflux in Fluconazole-Resistant Candida albicans Clinical Isolates

Holmes

Lin

Niimi

et al. 2008

Antimicrob Agents Chemother

149

134

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Fluconazole (FLC) remains the antifungal drug of choice for non-life-threatening Candida infections, but drug-resistant strains have been isolated during long-term therapy with azoles. Drug efflux, mediated by plasma membrane transporters, is a major resistance mechanism, and clinically significant resistance in Candida albicans is accompanied by increased transcription of the genes CDR1 and CDR2, encoding plasma membrane ABC-type transporters Cdr1p and Cdr2p. The relative importance of each transporter protein for efflux-mediated resistance in C. albicans, however, is unknown; neither the relative amounts of each polypeptide in resistant isolates nor their contributions to efflux function have been determined. We have exploited the pump-specific properties of two antibody preparations, and specific pump inhibitors, to determine the relative expression and functions of Cdr1p and Cdr2p in 18 clinical C. albicans isolates. The antibodies and inhibitors were standardized using recombinant Saccharomyces cerevisiae strains that hyper-express either protein in a host strain with a reduced endogenous pump background. In all 18 C. albicans strains, including 13 strains with reduced FLC susceptibilities, Cdr1p was present in greater amounts (2-to 20-fold) than Cdr2p. Compounds that inhibited Cdr1p-mediated function, but had no effect on Cdr2p efflux activity, significantly decreased the resistance to FLC of seven representative C. albicans isolates, whereas three other compounds that inhibited both pumps did not cause increased chemosensitization of these strains to FLC. We conclude that Cdr1p expression makes a greater functional contribution than does Cdr2p to FLC resistance in C. albicans.Factors identified as affecting the susceptibility of Candida albicans to azole antifungal drugs such as fluconazole (FLC) include overexpression or mutation of the drug target 14␣ lanosterol demethylase, mutations in other enzymes of the ergosterol pathway and increased expression of drug efflux pumps (reviewed in references 4, 40, and 53). Mediators of azole efflux from C. albicans include the major facilitator superfamily pumps Mdr1p (28) and Flu1p (1) and the ATPbinding cassette (ABC) transporters Cdr1p and Cdr2p (4, 52). Although FLC resistance clearly can be multifactorial, highlevel, clinically relevant resistance (MIC Ն 64 g ml Ϫ1 ) is most often associated with increased expression of mRNAs from the ABC genes CDR1 and CDR2 (3, 34, 37, 38). Analysis of resistance in clinical isolates has, to date, focused almost exclusively on measuring gene transcription, initially by Northern analysis (22,41,53), and more recently by transcript profiling and quantitative reverse transcription-PCR (16,34,38,55) and the use of reporter genes (24). However, the ability to compare the amounts of expressed Cdr polypeptides and, more importantly, the efflux activities of Cdr1p and Cdr2p, is crucial if the contribution of each pump protein to drug efflux function in clinical resistance is to be determined. Unfortunately, proteomic approaches using...

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Quinazolinone fungal efflux pump inhibitors. Part 3: (N-methyl)piperazine variants and pharmacokinetic optimization

Cited by 22 publications

References 7 publications

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

Microbial Efflux Pump Inhibition: Tactics and Strategies

ABC Transporter Cdr1p Contributes More than Cdr2p Does to Fluconazole Efflux in Fluconazole-Resistant Candida albicans Clinical Isolates

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