Aminoglycosides are broad-spectrum antibiotics used for treatment of serious bacterial infections, including the deadly tuberculosis and those accompanying AIDS, cystic fibrosis, and cancer. The emergence of pathogens resistant to these drugs represents a major threat to public health and underscores the need for new antimicrobial agents.
In Aim 1, we propose to utilize aminoglycoside-modifying enzymes of the aminoglycoside acetyltransferase (AAC) family in conjunction with a newly developed 6'-N-acylation protecting group-free chemical methodology (i) to generate in vitro libraries of new and more potent N-acylated aminoglycoside antibiotics, and (ii) to develop aminoglycoside probes that will serve as baits for identification of novel therapeutic protein targets/pathways for these antibiotics. Our chemoenzymatic and chemical strategies offer an effective solution to the following problems: (i) there are no existing general synthetic methodologies for the creation of N-acylated aminoglycosides, and (ii) there are no efficient methods to chemically modify specific amine groups on an aminoglycoside that contains a series of chemically identical amines. A few existing examples that use solely chemical syntheses are too demanding on research time and cost and are limited to very specific cases.
In Aim 2, we propose biochemical and structural studies of the mechanism of action and inhibition of a major determinant of aminoglycoside resistance in extensively drug-resistant strains of M. tuberculosis (XDR-TB). We expect this work to (i) advance the basic understanding of AG resistance of a variety of pathogenic bacteria, including M. tuberculosis, and (ii) provide a potential solution to overcome the aminoglycoside resistance problem in majority of XDR- TB. Relevance to public health: We expect that this work will contribute to the development of novel antibiotics with a potential to combat existing and newly emerging drug-resistant bacteria.

Public Health Relevance

The proposed research is relevant to public health as an improved understanding of aminoglycoside- resistance enzymes is expected to lead to the discovery and development of new drugs and also in identifying drug targets. This research will enable us to better handle the problem of resistance of infectious bacteria to aminoglycoside antibiotics. The proposed research will have a major impact in two ways: (1) our novel chemical and chemoenzymatic methodologies for the rapid and facile regio- selective N-acylation of aminoglycosides will greatly reduce the cost and effort generally associated with such modifications, and (2) our study of the mechanism of action and inhibition of the major determinant of aminoglycosdie resistance in extensively drug-resistant M. tuberculosis will advance our understanding of drug resistance and also set a new paradigm of aminoglycoside acetyltransferase in the antibiotics field.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI090048-02
Application #
8307324
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2011-08-01
Project End
2013-03-31
Budget Start
2012-08-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$315,788
Indirect Cost
$112,709
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Jin, Yi; Watkins, Derrick; Degtyareva, Natalya N et al. (2016) Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity. Medchemcomm 7:164-169
McKeating, Kristy S; Couture, Maxime; Dinel, Marie-Pier et al. (2016) High throughput LSPR and SERS analysis of aminoglycoside antibiotics. Analyst 141:5120-6
Fosso, Marina Y; McCarty, Katie; Head, Elizabeth et al. (2016) Differential Effects of Structural Modifications on the Competition of Chalcones for the PIB Amyloid Imaging Ligand-Binding Site in Alzheimer's Disease Brain and Synthetic Aβ Fibrils. ACS Chem Neurosci 7:171-6
Ngo, Huy X; Shrestha, Sanjib K; Garneau-Tsodikova, Sylvie (2016) Identification of Ebsulfur Analogues with Broad-Spectrum Antifungal Activity. ChemMedChem 11:1507-16
Chandrika, Nishad Thamban; Shrestha, Sanjib K; Ngo, Huy X et al. (2016) Synthesis and investigation of novel benzimidazole derivatives as antifungal agents. Bioorg Med Chem 24:3680-6
Willby, Melisa J; Green, Keith D; Gajadeera, Chathurada S et al. (2016) Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis. ACS Chem Biol 11:1639-46
Holbrook, Selina Y L; Garneau-Tsodikova, Sylvie (2016) Expanding Aminoglycoside Resistance Enzyme Regiospecificity by Mutation and Truncation. Biochemistry 55:5726-5737
Chandrika, Nishad Thamban; Garneau-Tsodikova, Sylvie (2016) A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides. Medchemcomm 7:50-68
Ngo, Huy X; Garneau-Tsodikova, Sylvie; Green, Keith D (2016) A complex game of hide and seek: the search for new antifungals. Medchemcomm 7:1285-1306
Garneau-Tsodikova, Sylvie; Labby, Kristin J (2016) Mechanisms of Resistance to Aminoglycoside Antibiotics: Overview and Perspectives. Medchemcomm 7:11-27

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