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The rise of antibacterial-resistant bacteria is a major problem in the United States of America and around the world. Millions of patients are infected with antimicrobial resistant bacteria each year. Novel antibacterial agents are needed to combat the growing and present crisis. Acetyl-CoA carboxylase (ACC), the multi-subunit complex which catalyses the first committed step in fatty acid synthesis, is a validated target for antibacterial agents. However, there are at present, no commercially available antibiotics that target ACC. Ethyl 4-[[2-chloro-5-(phenylcarbamoyl)phenyl]sulfonylamino]benzoate (SABA1) is a compound that has been shown to have antibacterial properties against Pseudomonas aeruginosa and Escherichia coli. SABA1 inhibits biotin carboxylase (BC), the enzyme that catalyses the first half reaction of ACC. SABA1 inhibits BC via an atypical mechanism. It binds in the biotin binding site in the presence of ADP. SABA1 represents a potentially new class of antibiotics that can be used to combat the antibacterial resistance crisis. [ABSTRACT FROM AUTHOR]

Acetyl-CoA carboxylase catalyzes the first committed and regulated step in fatty acid synthesis in all animals, plants and bacteria. In most Gram-positive and Gram-negative bacteria, the enzyme is composed of three proteins: biotin carboxylase, biotin carboxyl carrier protein and carboxyltransferase. The reaction consists of two half-reactions. The first half reaction is catalyzed by biotin carboxylase and involves the carboxylation of the vitamin biotin which is covalently attached to the biotin carboxyl carrier protein. The second half reaction catalyzed by carboxyltransferase involves the transfer of the carboxyl group from biotin to acetyl-CoA to form malonyl-CoA. This chapter will describe the inhibitors of both the biotin carboxylase and carboxyltransferase components of bacterial acetyl-CoA carboxylase. Inhibitors that were used in the elucidation of the structure and mechanism of the enzyme will be discussed first. The second half will focus on inhibitors that also possess antibacterial activity., (Copyright © 2024. Published by Elsevier Inc.)