Lessons in Discovery from Lynn Silver + Pro-con on alternatives to antibiotics

Dear All:

“Good decisions come from experience, and experience comes from bad decisions … and paying attention.”

You’ve probably heard the first part of that before, but the “… and paying attention” is my addition and reflection upon reading Lynn Silver’s most recent commentary in the Springer Series Topics in Medicinal Chemistry, edited by Jed Fisher, Marvin Miller and Shahriar Mobashery. Entitled “The Antibiotic Future,” it is a discussion of the hurdles of antibiotic discovery and a summary of Lynn’s far-ranging & pithy insights. It’s not open access so you’ll have to download yourself, but here’s the link and the abstract:

• Cite: Silver LL. The Antibiotic Future. In: Fisher J, Miller M, Mobashery S, editors. Topics in Medicinal Chemistry. Berlin, Heidelberg: Springer Berlin Heidelberg; 2017. p. 1-37.
• Link: https://link.springer.com/chapter/10.1007/7355_2017_24
• Abstract: Will the future of antibacterial therapy rely on an ongoing pipeline of new small molecule, direct-acting antibacterial agents that inhibit or kill bacterial pathogens, referred to here as antibiotics? What role will these small-molecule antibiotics have in the control of the bacterial infections of the future? Although there is today increased activity in the field of new antibiotic discovery, the history of this field over the past 30 years is a history of low output. This low output of new antibiotics does not encourage confidence that they can be central to the future control of bacterial infection. This low productivity is often blamed upon financial disincentives in the pharmaceutical industry, and on regulatory difficulties. But I believe that a critical underlying reason for the dearth of novel products is the fundamental difficulty of the science, coupled with a failure to directly grapple with the key scientific challenges that prevent forward motion. The future fate of antibiotic discovery will depend upon the degree to which the rate limiting steps of discovery are fully recognized, and the discovery technology turns to overcoming these blockades.

In the paper, Lynn covers everything from alternatives to antibiotics (see also below), natural products, the problem of frequency of resistance, combinations, the question of new vs. old targets, and more. This paper is great tour of the entire area and you’ll learn something from it whether you are new to the field or an old hand.

Lynn is truly a master of this field and she has over the years written many instructive papers. Just below, I provide a list of some of my favorites from her published works. If you’re doing drug discovery and haven’t explored her writings, I strongly encourage you to take an afternoon to study them in detail. I especially recommend the 2011 paper in CMR:

• Silver LL. Challenges of antibacterial discovery. Clin Microbiol Rev. 2011;24(1):71-109.
  • Link: https://journals.asm.org/doi/10.1128/CMR.00030-10
  • This is free to download at the link
• Silver LL. A Gestalt approach to Gram-negative entry. Bioorg Med Chem. 2016; 24:6379-6389.
  • Link: http://www.sciencedirect.com/science/article/pii/S0968089616304679
  • Not free to download … you’ll need to get it via your library
• Silver LL: Antibacterials for any target. Nature Biotech 11:1102-4, 2014.
  • A commentary on RNA-guided nucleases in particular but also on narrow-spectrum antibacterials. Not free … you’ll need to get via your library
• Papers on natural products (neither is free — use your library to access)
  • 2008 Expert Opin Drug Disc: Natural products for antibacterials
  • 2015 Future Medicine: Natural products as a source of drug leads

Finally, and if you’re interested in non-antibiotic alternative approaches, Lynn’s comments on this area may make you want to dig further. A good place to start would be with the 3 papers below — collectively, they provide a good set of pro-con comments on the challenges of this strategy. The alternatives that seek to work in combination or as enhancers are going to be very tricky to develop and it’s important to understand the issues:

• Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H, Fischetti VA, et al. Alternatives to antibiotics-a pipeline portfolio review. Lancet Infect Dis. 2016;16(2):239-51.
  • Link: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00466-1/fulltext
  • This is free to download at the link
• Dickey SW, Cheung GYC, Otto M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov. 2017;16(7):457-71.
  • Link: https://www.nature.com/nrd/journal/v16/n7/full/nrd.2017.23.html
  • Not free to download … you’ll need to get it via your library
• Tse BN, Adalja AA, Houchens C, Larsen J, Inglesby TV, Hatchett R. Challenges and Opportunities of Nontraditional Approaches to Treating Bacterial Infections. Clinical Infectious Diseases. 2017;65(3):495-500.
  • Link: https://academic.oup.com/cid/article-abstract/doi/10.1093/cid/cix320/3737651/Challenges-and-Opportunities-of-Nontraditional
  • Not free to download … you’ll need to get it via your library
• Post-newsletter addition: This 6 Aug 2019 newsletter discusses a pair of useful papers that discuss the special challenges of non-traditional products.

In short, knowing what has come before is the only way that I know to avoid repeating past mistakes. If you’re going to make a mistake, please make a new one … it’s much more productive! Many thanks to Lynn for sharing her insights via these publications.

Best wishes,

–jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Chief Strategy Officer, CARB-X | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: http://amr.solutions/blog.html

Upcoming meetings of interest to the AMR community:

• 5-8 Sep 2017: ASM-ESCMID conference on antibiotic R&D, including the CARB-X + GARDP Antibiotic Bootcamp
• 13 Sep 2017 (DC): FDA-CDRH workshop on diagnostic devices for detecting antimicrobial susceptibility & resistance
• 4-8 Oct 2017 (San Diego): IDWeek
• 29 Oct-1 Nov 2017 (Santa Fe): Keystone Symposium – Antimicrobials and Resistance: Opportunities and Challenges
• 24-27 Nov 2017 (Taipei): 30th International Congress of Chemotherapy & Infection (ICC)
• 12-14 Feb 2018 (Baltimore): ASM Biothreats Conference
• 11-16 Mar 2018 (Ventura Beach): Gordon Research Conference on Antibacterial Discovery
• 21-24 Apr 2018 (Madrid): ECCMID
• 7-11 Jun 2018 (Atlanta): ASM Microbe
• 22-27 Jul 2018 (Bryant University, Smithfield, RI): Gordon Research Conference on Drug Resistance for Cancer, Infectious Disease and Agriculture