Resistance mapping and mode of action of a novel class of antibacterial anthranilic acids: evidence for disruption of cell wall biosynthesis

• Published in: Journal of antimicrobial chemotherapy Vol. 62; no. 4; pp. 720 - 729
• Main Authors: Mott, John E., Shaw, Bailin A., Smith, James F., Bonin, Paul D., Romero, Donna L., Marotti, Keith R., Miller, Alita A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.2008; Oxford Publishing Limited (England)
• Subjects: Anti-Bacterial Agents - pharmacology; antibiotic discovery; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria; Bacterial diseases; Bacterial Proteins - genetics; Biological and medical sciences; Cell Wall - drug effects; Cellular biology; DNA Mutational Analysis; Drug resistance; Drug Resistance, Bacterial; Genes, Bacterial; Genes, Essential; HTS; Human bacterial diseases; Infectious diseases; Inhibitor drugs; Medical sciences; Membrane Proteins - genetics; Microbial Sensitivity Tests; ortho-Aminobenzoates - pharmacology; Pharmacology. Drug treatments; Protein synthesis; Staphylococcal infections, streptococcal infections, pneumococcal infections; Staphylococcus aureus; Staphylococcus aureus - drug effects; Transduction, Genetic; antibiotic discovery; HTS; Cartography; Biosynthesis; Cell wall; Infection; Resistance; Antibiotic; Aminoacid; Bacteriosis; Bacteria; Micrococcales; Micrococcaceae; Antibacterial agent; Mechanism of action; Staphylococcal infection; Anthranilic acid; Staphylococcus aureus
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkn261

Objectives The aim of this study was to characterize the mechanism of action of a novel class of bacterial protein synthesis inhibitors identified in a high-throughput coupled transcription–translation assay. Methods Evaluation of the cross-resistance to antibiotics with known mechanisms of action, resistance mapping and biochemical characterization of a novel class of antibacterial anthranilic acids was performed. Results No cross-resistance to established classes of antibiotics was found. Resistance was mapped to SA1575, an essential, integral membrane protein predicted to be involved in polysaccharide biosynthesis. Biochemical analysis demonstrated the inhibition of cell wall biosynthesis. Conclusions This novel class of antibacterial anthranilic acids inhibits cell wall biosynthesis. Resistance mapped to SA1575, which may represent a novel target for antibacterial drug discovery.