The frequency of antibiotic-resistant bacteria is currently rising at an alarming rate. It is estimated that greater than 1.7 million hospital-acquired bacterial infections occurred in 2008, resulting in more than 100,000 deaths. The estimated costs on the U.S. health care budget attributed to these infections are $5 billion annually. Clinicians are increasingly concerned about the threat of Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumanii and the Enterobacteriacaeae, the main causes of hospital-acquired pneumonia. In a recent CDC survey 26% of P. aeruginosa isolates and 37% of A. baumanii hospital-isolates were resistant to the most common antibiotic treatments. While there have been a few recently approved clinical candidates for Gram-positive pathogens, new treatments for Gram-negative pathogens have stalled in recent decades. Thus, the need for antibiotics that are effective against Gram-negative infections has become a medical necessity. To that end, we have identified and characterized a new natural product, mangrolide A, which exhibits potent and selective bactericidal activity against Gram-negative pathogens, including those associated with cystic fibrosis and hospital-acquired pneumonia infections with MICs ranging from 0.4 to 2.4 g/mL, with >20 g/mL activity against Gram-positive pathogens. Mechanism of action studies revealed that interferes with the ribosomal proofreading process, leading to an increased rate of error in protein synthesis. This is the first example of a macrolide glycoside structure displaying the mechanism of action found for aminoglycosides. Structurally, mangrolide A contains an 18-membered macrolide ring containing five olefins and three oxymethines adorned with a disaccharide unit composed of mycaminose and 2,4-di-O-methyl-6-deoxyglucose. Based on the unique anti-microbial selectivity profile and synthetic tractability, we propose a total synthesis of mangrolide A and disaccharide-modified variants to generate mangrolide analogs. These analogs will be evaluated against a panel of Gram-negative pathogens including clinical isolates. We already demonstrated that mangrolide does not cause nephrotoxicity, thus eliminating one major hurdle for the development of improved candidates for the treatment of Gram- negative pathogens. The proposed studies will provide lead compounds for the treatment of pneumonia and sepsis infections caused by Gram-negative pathogens.

Public Health Relevance

This application proposes the synthesis and biological evaluation of the novel macrolide antibiotic Mangrolide A, a new Gram-selective antibiotic with aminoglycoside mode-of- action. Our combined chemical and biological approach aims to provide a collection of mangrolide-based leads for Gram-negative pneumonal infections. The proposed research is highly relevant because of hospital-acquired pneumonia caused by drug- resistant Gram-negative pathogens.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM111329-01A1
Application #
8961771
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390