Chapter 6

Recent Advances in the Discovery and Development of New Drugs Against Gram-Negative Pathogens

Ashok Rattan, V. Samuel Raj and Kulvinder S. Saini

Abstract

In the 20th century, particularly in the 1950s and 1960s, the discovery and development of antimicrobial agents along with stringent vaccination schedule and improved hygiene led to tremendous improvements in life expectancy globally. However, in the last 20 years, it is distressing to observe that bacterial resistance has emerged as a major threat and some authorities are warning about a return to the preantibiotic era, where even trivial infections could prove life threatening. In developing countries, neglected diseases kill more than half a million people annually, and inflict severe economic, psychological and physical damage in much larger populations. In the last decade, advances in our understanding of molecular physiology and genomics of these pathogens along with significant advances in Medicinal Chemistry (e.g., computer–aided drug design) and Biotechnology have ushered an exciting era of new drug discovery research. For a long time, the major pharmaceutical companies focused their attention towards discovering new drugs primarily against Gram-positive pathogens, and recently there appears to be renewed research and development efforts focused on multidrug resistant Gram-negative pathogens. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are responsible for multidrug resistant nosocomial infections and resistance of these clinical isolates to antimicrobial agents presents serious therapeutic dilemmas for physicians. Infectious diseases can be difficult to diagnose, the causative agent may not be clinically apparent and untreated infections can have dire consequences. Latest strategies to prevent the emergence and spread of antimicrobial resistance and to “re-engineer” the effective life of available drugs are urgently required. Medical practitioners and researchers should optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, selection of pathogenic organisms and emergence of resistance. Given the association between antimicrobial use and the selection of resistance pathogens, the frequency of inappropriate use of antimicrobials is often used as a surrogate marker for the avoidable impact of antibiotic resistance. This review will outline recent progress made globally in the discovery and development of new drugs against Gram-negative pathogens.

Total Pages: 237-262 (26)

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