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Designer broad-spectrum polyimidazolium antibiotics.

ABSTRACT: For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.

SUBMITTER: Zhong W

PROVIDER: S-EPMC7739875 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Designer broad-spectrum polyimidazolium antibiotics.

Zhong Wenbin W Shi Zhenyu Z Mahadevegowda Surendra H SH Liu Bo B Zhang Kaixi K Koh Chong Hui CH Ruan Lin L Chen Yahua Y Zeden Merve S MS Pee Carmen J E CJE Marimuthu Kalisvar K De Partha Pratim PP Ng Oon Tek OT Zhu Yabin Y Chi Yonggui Robin YR Hammond Paula T PT Yang Liang L Gan Yunn-Hwen YH Pethe Kevin K Greenberg E Peter EP Gründling Angelika A Chan-Park Mary B MB

Proceedings of the National Academy of Sciences of the United States of America 20201123 49

For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activ ...[more]

PMID: 33229526

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Project description:BackgroundThe gut microbiome (GMB) generates numerous small chemicals that can be absorbed by the host and variously biotransformed, incorporated, or excreted. The resulting metabolome can provide information about the state of the GMB, of the host, and of their relationship. Exploiting this information in the service of biomarker development is contingent on knowing the GMB-sensitivity of the individual chemicals comprising the metabolome. In this regard, human studies have lagged far behind animal studies. Accordingly, we tested the hypothesis that serum levels of chemicals unequivocally demonstrated to be GMB-sensitive in rodent models would also be affected in a clinical patient sample treated with broad spectrum antibiotics.MethodsWe collected serum samples from 20 hospitalized patients before, during, and after treatment with broad-spectrum antibiotics. We also collected samples from 5 control patients admitted to the hospital but not prescribed antibiotics. We submitted the samples for a non-targeted metabolomic analysis and then focused on chemicals known to be affected both by germ-free status and by antibiotic treatment in the mouse and/or rat.ResultsPutative identification was obtained for 499 chemicals in human serum. An aggregate analysis did not show any time x treatment interactions. However, our literature search identified 10 serum chemicals affected both by germ-free status and antibiotic treatment in the mouse or rat. Six of those chemicals were measured in our patient samples and additionally met criteria for inclusion in a focused analysis. Serum levels of 5 chemicals (p-cresol sulfate, phenol sulfate, hippurate, indole propionate, and indoxyl sulfate) declined significantly in our group of antibiotic-treated patients but did not change in our patient control group.ConclusionsBroad-spectrum antibiotic treatment in patients lowered serum levels of selected chemicals previously demonstrated to be GMB-sensitive in rodent models. Interestingly, all those chemicals are known to be uremic solutes that can be derived from aromatic amino acids (L-phenylalanine, L-tyrosine, or L-tryptophan) by anaerobic bacteria, particularly Clostridial species. We conclude that judiciously selected serum chemicals can reliably detect antibiotic-induced suppression of the GMB in man and thus facilitate further metabolome-based biomarker development.

Project description:ObjectiveThe aim of this study is to describe the proportion of children hospitalized with urinary tract infections (UTIs) who receive initial narrow- versus broad-spectrum antibiotics across children's hospitals and explore whether the use of initial narrow-spectrum antibiotics is associated with different outcomes.Design, setting and participantsWe performed a retrospective cohort analysis of children aged 2 months to 17 years hospitalized with UTI (inclusive of pyelonephritis) using the Pediatric Health Information System (PHIS) database.Main outcome and measuresWe analyzed the proportions of children initially receiving narrow- versus broad-spectrum antibiotics; additionally, we compiled antibiogram data for common uropathogenic organisms from participating hospitals to compare with the observed antibiotic susceptibility patterns. We examined the association of antibiotic type with adjusted outcomes including length of stay (LOS), costs, and 7- and 30-day emergency department (ED) revisits and hospital readmissions.ResultsWe identified 10,740 hospitalizations for UTI across 39 hospitals. Approximately 5% of encounters demonstrated initial narrow-spectrum antibiotics, with hospital-level narrow-spectrum use ranging from <1% to 25%. Approximately 80% of hospital antibiograms demonstrated >80% Escherichia coli susceptibility to cefazolin. In adjusted models, those who received initial narrow-spectrum antibiotics had shorter LOS (narrow-spectrum: 33.1 [95% confidence interval; CI]: 30.8-35.4] h vs. broad-spectrum: 46.1 [95% CI: 44.1-48.2] h) and reduced costs (narrow-spectrum: $4570 [$3751-5568] versus broad-spectrum: $5699 [$5005-$6491]). There were no differences in ED revisits or hospital readmissions. In summary, children's hospitals have low rates of narrow-spectrum antibiotic use for UTIs despite many reporting high rates of cefazolin-susceptible E. coli. These findings, coupled with the observed decreased LOS and costs among those receiving narrow-spectrum antibiotics, highlight potential antibiotic stewardship opportunities.

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Designer broad-spectrum polyimidazolium antibiotics.

Publications

Designer broad-spectrum polyimidazolium antibiotics.

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