The introduction of antibiotics into clinical use was a significant medical breakthrough of the 20th century, enabling modern medical procedures such as cancer treatment, organ transplants, and open-heart surgery. However, misuse of these valuable compounds has led to the rapid rise of antimicrobial resistance (AMR), with some infections now untreatable. Policymakers are acknowledging the threat of a post-antibiotic era and promising additional grant funding, driving a resurgence of interest in antibiotic discovery and development. The UK Government-commissioned O'Neill report predicts that 10 million people a year will die from drug-resistant infections by 2050 without urgent action. To develop a new generation of anti-infective drugs, the best hope is to discover new microbial natural products (NPs), which are unrivalled in their chemical diversity and effectiveness as antibiotics. Filamentous actinomycetes make 64% of the known NP antibiotic classes, while the remainder are made by other bacteria and fungi. The development of anti-infective drugs and the concept of chemotherapy is widely accredited to Paul Ehrlich, who developed the synthetic arsenic-based pro-drugs salvarsan and neo-salvarsan around 100 years ago to treat Treponema pallidum, the causative agent of syphilis.Penicillin was developed by Norman Heatley, Howard Florey, and Ernst Chain at Oxford, who played a crucial role in its development as a drug. Dorothy Hodgkin solved the beta-lactam structure in 1945, enabling the development of semi-synthetic derivatives to bypass penicillin resistance. Antibiosis between microbes was already known before penicillin's discovery, and the first clinical use of antibiotics was reported in the 1890s with a pyocyanase extract.
During the Golden Age of antibiotic discovery, new antibiotic classes were discovered yearly from soil samples. However, compound rediscovery became a problem. Recently, new antibiotic-producing strains in under-explored environments and new genome mining tools have revived the field.
As of December 2018, there are 45 new antibiotic candidates in clinical trials for the US market, with 28 belonging to known NP classes and 17 synthetic, comprising 12 classes. Seven are new. The NP classes include 13 beta-lactams, five variant beta-lactams, two hybrids, and seven combinations with beta-lactamase inhibitors. There are five new tetracyclines, five aminoglycosides, distamycin, fusidane, macrolide, pleuromutilin, and polymyxins. Two new synthetic classes are in Phase III clinical trials: ridinilazole and murepavidin. However, this is still a modest number for the therapeutic area.
The rise in antibiotic-resistant bacteria has prompted governments to address the issue, prompting the UK government to appoint economist Lord Jim O'Neill to lead a strategic review. The economics of antibiotic R&D are a major disincentive to investment, and innovative solutions are needed to delink revenue from drug sales. New chemical matter (NPs) are the most likely source of new materials for antibiotic discovery, with thousands of NP antibiotics awaiting discovery across the bacterial kingdom. Advances in CRISPR/Cas9-mediated genome editing are available, and recent advances have led to the discovery of many new molecular structures with exceptional biological activities. With suitable global action, a renewed antibiotic pipeline to combat AMR alongside other emerging technologies should be developed.
By Vanaja Kholgade
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