Marcel Faber Roundtable: Is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration?
- 1.1k Downloads
There are few new antibiotics in the pipeline today. The reasons may include starvation at the front of the pipeline due to inadequate sources of suitable compounds to screen coupled with poorly validated discovery methodologies. A successful antibiotic discovery approach in the past, based upon whole cell antibiotic screening of natural products from actinomycetes and fungi, eventually suffered from constipation in the middle of the pipeline due to rediscovery of known compounds, even though low throughput methodology was employed at the front end. The current lack of productivity may be attributed to the poor choice of strategies to address the discovery of new antibiotics. Recent applications of high throughput in vitro screening of individual antibacterial targets to identify lead compounds from combinatorial chemical libraries, traditional chemical libraries, and partially purified natural product extracts has not produced any significant clinical candidates. The solution to the current dilemma may be to return to natural product whole cell screening. For this approach to work in the current millennium, the process needs to be miniaturized to increase the throughput by orders of magnitude over traditional screening, and the rediscovery of known antibiotics needs to be minimized by methods that can be readily monitored and improved over time.
KeywordsActinomycetes Antibiotics Natural products Streptomyces
I thank Linda Lasure for inviting me to participate in the Marcel Faber Roundtable discussion on the pharmaceutical pipeline. I also thank Cubist Pharmaceuticals, Inc., for support, and Jared Silverman for comments on the manuscript.
- 1.Arai T (1976) Actinomycetes: the boundary microorganisms. Toppan Company Limited, Tokyo, pp 561–651Google Scholar
- 2.Baltz RH (2005) Natural product discovery and development at Eli Lilly and Company: one scientist’s view. SIM News 55:5–16Google Scholar
- 3.Baltz RH (2005) Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall. SIM News 55:186–196Google Scholar
- 4.Baltz RH, Brian P, Miao V, Wrigley SW (2005) Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus. J Ind Microbiol Biotechnol (in press)Google Scholar
- 7.Bossidy L, Charan R (2002) Execution: the discipline of getting things done. Crown Business, New YorkGoogle Scholar
- 11.Hahn DR, Gustafson G, Waldron C, Bullard B, Jackson JD, Mitchell J (2005) Butenyl-spinosyns, a natural example of genetic engineering of antibiotic biosynthetic genes. J Ind Microbiol Biotechnol (in press)Google Scholar
- 13.Kahn EJ Jr (1976) All in a century: the first 100 years of Eli Lilly and Company. Eli Lilly and Company, IndianapolisGoogle Scholar
- 14.Kouzes JM, Prosner BZ (2002) The leadership challenge, 3rd edn. Jossey-Bass, New YorkGoogle Scholar
- 15.Lazzirini A, Cavaletti L, Toppo G, Marinelli F (2001) Rare genera of actinomycetes as potential producers of new antibiotics. Antonie Van Leeuwenhoek 79:399–405Google Scholar
- 19.Penn J, Li X, Whiting A, Latif M, Gibson T, Silva CJ, Brian P, Davies J, Miao V, Wrigley SW, Baltz RH (2005) Heterologous production of daptomycin in Streptomyces lividans. J Ind Microbiol Biotechnol (in press)Google Scholar
- 20.Strohl WR, Woodruff HB, Monaghan RL, Hendlin D, Mochales S, Demain AL, Liesch J (2001) The history of natural products research at Merck & Co., Inc. SIM News 51:5–19Google Scholar
- 21.Suzuki S-I, Okuda T, Komatsubara S (1999) Selective isolation and distribution of Sporichthya strains in soil. Appl Environ Microbiol 65:1930–1935Google Scholar
- 26.Waksman SA (1964) Streptomycin: background, isolation, properties, and utilization. Nobel Lecture, December 12, 1952. In: Nobel Lectures, Physiology or Medicine 1942–1962, Elsevier, Amsterdam, pp 370–388Google Scholar
- 30.Weinstein MJ (2004) Micromonospora antibiotic discovery at Schering/Schering Plough (1961–1973): a personal reminiscence. SIM News 54:56–66Google Scholar
- 31.Woodruff HB, McDaniel LE (1958) The antibiotic approach. In: Cohen ST, Rowatt R (eds) The strategy of chemistry, Cambridge University Press, Cambridge, pp 29–48Google Scholar