Chapter 15 - Emerging New Therapeutics Against Key Gram-Negative Pathogens

Abstract

Publisher Summary This chapter focuses on compounds in late preclinical and clinical development and compounds derived from known and new classes of antibiotics that show promising activity against multidrug-resistant (MDR) gram-negative bacteria. A major emphasis is on compounds that exhibit a new mechanism of action and on anti-pseudomonal antibiotics. In addition, particular attention is devoted to strategies that move away from the older model of identifying broad-spectrum antibiotics in favor of more focused, narrow-spectrum approaches. Antibiotic drug discovery in the past decades has focused efforts on the development of antibiotics against gram-positive bacteria and more specifically against multidrug-resistant Staphylococcus aureus ( S . aureus ). In contrast, treatment options against some MDR gram-negative pathogens have become very limited, especially due to the emergence of resistance against the last resort antibiotics, colistin and polymyxin B. Compounding the problem of limited financial resources is the fact that gram-negative organisms are inherently difficult to kill. This is due in part to their outer membrane (OM), which is composed of 75% of lipopolysaccharides (LPSs). LPSs are negatively charged, which makes the OM of gram-negative bacteria highly impermeable for many classes of antibiotics, thereby providing the gram-negative bacteria with a formidable shield to prevent entry of antibacterials. Moreover, these organisms are highly efficient at upregulating, mutating, or acquiring genes that code for mechanisms of antibiotic resistance. Most of the antibacterial compounds in preclinical and early development are derived from established classes. Within the established drug classes, novel β lactam antibiotics containing iron-chelating groups are promising.