Abstract

The emergence of multiple drug resistant pathogens is becoming problematic worldwide, and the discovery of new antibiotics continues to decline. The broad, long-term objective of this proposal is to discover, characterize, and develop a new structural class of antibiotics-nucleoside antibiotics-that target bacterial translocase I involved in peptidoglycan cell wall biosynthesis.
The specific aims of this proposal are (I) to characterize the assembly and incorporation of the aminoribosyl moiety found within the family of lipopeptidyl-nucleoside antibiotics and (II) to functionally and mechanistically characterize enzymes catalyzing novel or unusual biochemical reactions represented herein by a new family of serine hydroxymethyltransferase-like enzymes that are hypothesized to catalyze an aldol-type condensation to form unusual nonproteinogenic amino acids.
Specific Aim I and II will be achieved by using the robust genetic system developed for the lipopeptidyl nucleoside A-90289-producing strain for in vivo studies employing gene inactivation and cross-complementation, and recombinant proteins will be exploited for functional and mechanistic studies in vitro. The results will establish a new mechanism for incorporating ribosyl units into natural product scaffolds and will establish a paradigm for the entry into high-carbon nucleoside antibiotics. The results will be essential for our long-term goals of searching for new nucleoside antibiotics using genetic information (a genotype-to-chemotype approach), will allow for the structural diversification of the parent scaffolds using combinatorial biosynthesis and total synthesis, and will provide the basis for the design of second generation antibiotics with improved biocompatibility and pharmacological properties.

Public Health Relevance

Diseases caused by multidrug resistant bacteria are becoming a significant threat to human health worldwide. The goal of this proposal is to study nucleoside antibiotics that represent a new structural class of antibiotics, have a different mode of action than clinically used antibacterial drugs, and are in general not toxic to animals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI087849-02
Application #
8281422
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Xu, Zuoyu
Project Start
2011-06-15
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$429,934
Indirect Cost
$117,434

  Institution

Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Koppermann, Stefan; Cui, Zheng; Fischer, Patrick D et al. (2018) Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics. ChemMedChem 13:779-784
Cui, Zheng; Wang, Xia-Chang; Liu, Xiaodong et al. (2018) Self-Resistance during Muraymycin Biosynthesis: a Complementary Nucleotidyltransferase and Phosphotransferase with Identical Modification Sites and Distinct Temporal Order. Antimicrob Agents Chemother 62:
Huang, Ying; Liu, Xiaodong; Cui, Zheng et al. (2018) Pyridoxal-5'-phosphate as an oxygenase cofactor: Discovery of a carboxamide-forming, ?-amino acid monooxygenase-decarboxylase. Proc Natl Acad Sci U S A 115:974-979
Cui, Zheng; Liu, Xiaodong; Overbay, Jonathan et al. (2018) Enzymatic Synthesis of the Ribosylated Glycyl-Uridine Disaccharide Core of Peptidyl Nucleoside Antibiotics. J Org Chem 83:7239-7249
Goswami, Anwesha; Liu, Xiaodong; Cai, Wenlong et al. (2017) Evidence that oxidative dephosphorylation by the nonheme Fe(II), ?-ketoglutarate:UMP oxygenase occurs by stereospecific hydroxylation. FEBS Lett 591:468-478
Liu, Xiaodong; Jin, Yuanyuan; Cai, Wenlong et al. (2016) A biocatalytic approach to capuramycin analogues by exploiting a substrate permissive N-transacylase CapW. Org Biomol Chem 14:3956-62
Kulkarni, Aditya; Zeng, Yu; Zhou, Wei et al. (2016) A Branch Point of Streptomyces Sulfur Amino Acid Metabolism Controls the Production of Albomycin. Appl Environ Microbiol 82:467-77
Liu, Xiaodong; Jin, Yuanyuan; Cui, Zheng et al. (2016) The Role of a Nonribosomal Peptide Synthetase in l-Lysine Lactamization During Capuramycin Biosynthesis. Chembiochem 17:804-10
Cai, Wenlong; Wang, Xiachang; Elshahawi, Sherif I et al. (2016) Antibacterial and Cytotoxic Actinomycins Y6-Y9 and Zp from Streptomyces sp. Strain Gö-GS12. J Nat Prod 79:2731-2739
Cai, Wenlong; Goswami, Anwesha; Yang, Zhaoyong et al. (2015) The Biosynthesis of Capuramycin-type Antibiotics: IDENTIFICATION OF THE A-102395 BIOSYNTHETIC GENE CLUSTER, MECHANISM OF SELF-RESISTANCE, AND FORMATION OF URIDINE-5'-CARBOXAMIDE. J Biol Chem 290:13710-24

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