Chemical and Biological Optimization of a Gram negative Selective Antibiotic

Ut Southwestern Medical Center, Dallas TX

Investigators

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Abstract

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 µg/mL, with >20 µg/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.