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DCAP: a broad-spectrum antibiotic that targets the cytoplasmic membrane of bacteria.

ABSTRACT: Persistent infections are frequently caused by dormant and biofilm-associated bacteria, which often display characteristically slow growth. Antibiotics that require rapid cell growth may be ineffective against these organisms and thus fail to prevent reoccurring infections. In contrast to growth-based antimicrobial agents, membrane-targeting drugs effectively kill slow-growing bacteria. Herein we introduce 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP), a potent broad-spectrum antibiotic that reduces the transmembrane potential of Gram-positive and Gram-negative bacteria and causes mislocalization of essential membrane-associated proteins, including MinD and FtsA. Importantly, DCAP kills nutrient-deprived microbes and sterilizes bacterial biofilms. DCAP is lethal against bacterial cells, has no effect on red blood cell membranes, and only decreases the viability of mammalian cells after ?6 h. We conclude that membrane-active compounds are a promising solution for treating persistent infections. DCAP expands the limited number of compounds in this class of therapeutic small molecules and provides new opportunities for the development of potent broad-spectrum antimicrobial agents.

SUBMITTER: Eun YJ

PROVIDER: S-EPMC3516701 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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DCAP: a broad-spectrum antibiotic that targets the cytoplasmic membrane of bacteria.

Eun Ye-Jin YJ Foss Marie H MH Kiekebusch Daniela D Pauw Daniel A DA Westler William M WM Thanbichler Martin M Weibel Douglas B DB

Journal of the American Chemical Society 20120705 28

Persistent infections are frequently caused by dormant and biofilm-associated bacteria, which often display characteristically slow growth. Antibiotics that require rapid cell growth may be ineffective against these organisms and thus fail to prevent reoccurring infections. In contrast to growth-based antimicrobial agents, membrane-targeting drugs effectively kill slow-growing bacteria. Herein we introduce 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3- ...[more]

PMID: 22741745

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Project description:Urinary tract infections are among the most common bacterial infections in humans. Moreover, they are highly recurrent and increasingly often resistant to antibiotics. The antimicrobial properties of the amniotic membrane (AM), the innermost layer of fetal membranes, have been briefly reported in the literature, however, the results of published studies are often inconsistent and unclear; moreover, its effect on uropathogenic bacteria has not yet been investigated. Further, there is no data in the literature about the effect of AM preparation and storage on its antimicrobial properties. To examine the impact of several preparation procedures on the antimicrobial properties of AM, we prepared patches and homogenates of fresh (fAM) and cryopreserved (cAM) human AM and tested them on 14 selected Gram-positive and Gram-negative uropathogenic bacteria. By employing novel antimicrobial efficiency assays we showed that fAM and cAM homogenates have broad-spectrum antimicrobial activity against all here tested uropathogenic bacteria, except for Serratia marcescens. Moreover, they had a potent effect also on the multiple-resistant clinical strains of uropathogenic Escherichia coli. Interestingly, the patches of fAM and cAM had no antimicrobial effect on any of the tested strains. We therefore prepared and stored AM patches according to the standard procedure for clinical use in ophthalmology, which includes the cryopreservation of antibiotic-treated AM, and performed antimicrobial efficiency assays. Our findings suggest that the ultrastructure of AM patches could enable the retention of added antibiotics. In addition, we also prepared gentamicin-resistant uropathogenic E. coli strains, which confirmed that the antimicrobial effect of antibiotic-treated AM patches can be attributed to the antibiotic alone. To summarize, here we describe novel protocols for preparation and storage of AM to ensure the preservation of its antimicrobial factors. Moreover, we describe the mechanism of AM retention of antibiotics, based on which the AM could potentially be used as a drug delivery vehicle in future clinically applicable approaches.

Dataset Information

DCAP: a broad-spectrum antibiotic that targets the cytoplasmic membrane of bacteria.

Publications

DCAP: a broad-spectrum antibiotic that targets the cytoplasmic membrane of bacteria.

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