Chapter 16. Nonclassical Targets for Antibacterial Agents

This chapter discusses some examples of anti-bacterial agents that act on nonclassical targets. The murein lipoprotein is a major protein in the outer membrane of the gram-negative bacteria. This molecule is synthesized as a prolipoprotein in the cytoplasm, and is subsequently translocated across the cytoplasmic membrane by a signal peptide. The outer membrane is unique to the gram-negative bacteria, and it can provide a selective target for inhibition by antibiotics. Globomycin is a cyclic peptide antibiotic active against gram-negative bacteria. Bicyclomycin is another antibiotic selective against gram-negative bacteria. The lipopolysaccharide (LPS) of gram-negative bacteria consists of polysaccharide units linked to a lipid structure (lipid A) through 2-keto-3∼deoxyoctanoic acid (KDO). Arabinose 5-phosphate isomerase is required for the biosynthesis of KDO. Anti-bacterial agents are sometimes used in combination. The majority of combinations act on classical targets; however, there are several examples of combinations where one of the drugs has a unique mode of action that can be considered as nonclassical. Many antibiotics are unable to inhibit selected microbes because they are not able to penetrate through the outer layers of the bacterial cell. By virtue of their structure and chemical composition, these layers serve as a barrier and exclude certain antibiotics and other toxic agents. Although the antibiotic activity is usually directed against a classical target, inhibition of a drug-inactivating enzyme can be considered nonclassical. Several drugs are known that facilitate the activity of β-lactam antibiotics against 8-lactam-resistant bacteria by inhibiting β-lactamases and sparing the β-lactam antibiotic from enzymatic hydrolysis. Another approach to the treatment is the use of drugs that interfere with the pathogenesis of the disease. Compounds with this kind of activity would not necessarily have classical antibiotic activity but could be useful for treatment by interfering with a nonclassical, virulence target.