Peptidomimetics of D-Ala-D-Ala as Novel Antibacterials

Middle Tennessee State University, Murfreesboro TN

Investigators

Abstract

DESCRIPTION (provided by applicant): Although there are currently numerous antibacterial drugs on the market, many bacteria are becoming resistant to existing drugs, and the emergence of these drug-resistant microorganisms is a significant threat to public health. Virtually all classes of antibacterials in use have been circumvented to some extent by various resistance mechanisms and as a result there is a continual need for new structural classes of antibacterials. Penicillins are bacterial cell wall synthesis inhibitors and act by inhibition of Penicillin Binding Proteins (PBP's), also know as D-D-peptidases. The substrate for the D-D-peptidases is the cell wall peptidoglycan strand ending in D-alanine-D-alanine. However, penicillins and other drugs of that class were not designed to inhibit the D-D-peptidases. The objective of this application is to design and synthesize inhibitors of the D-D-peptidases as potential antibacterial drugs. Hydroxyethylene peptidomimetics of peptidic enzyme substrates such as the HIV protease substrate have been previously developed as drugs. A similar design concept should also apply to the D-D-peptidase substrate. The long-term objective of this project is to synthesize a series of peptidomimetics of the dipeptide D-alanine-D-alanine. These compounds will be tested for enzyme binding and for antibacterial activity. Various peptidomimetics have been designed and the syntheses of several have been initiated. Linear analogs of D-ala-D-ala containing a carboxylic acid will be synthesized, as will cyclopropyl analogs. Tetrazoles have been used successfully as bioisosteric replacements for the carboxylic acids in a number of drugs. An example is the angiotensin receptor antagonist Losartan. Along those lines, both linear and cyclopropyl analogs of D-ala-D-ala containing a tetrazole as a replacement for the carboxylic acid will be synthesized and tested for enzyme binding and antibacterial activity. The proposed compounds constitute an entirely new structural class of potential antibacterials and as such should possess activity against resistant organisms. This would have a significant impact in the ability to treat bacterial infections.