The Garden of Antimicrobial Delights

By Julian Davies The Garden of Antimicrobial Delights Major advances in genomics, cloning, and chemistry will restock the dwindling supply of effective antibiotics, but we can’t depend on big pharma and biotech. Green mold hyphae and fruiting structure, Aspergillus ustus. Dennis Kunkel Microscopy, Inc. / Visuals Unlimited, Inc. Almost all papers and reviews dealing with infectious diseases stress that new classes of antibiotic

Julian Davies
May 1, 2010

The Garden of Antimicrobial Delights

Major advances in genomics, cloning, and chemistry will restock the dwindling supply of effective antibiotics, but we can’t depend on big pharma and biotech.

Green mold hyphae and fruiting structure, Aspergillus ustus.
Dennis Kunkel Microscopy, Inc. / Visuals Unlimited, Inc.

Almost all papers and reviews dealing with infectious diseases stress that new classes of antibiotics are badly needed to treat the increasing number of common and emerging cases of infection due to antibiotic-resistant organisms, be they bacteria, viruses, or parasites. What happened to the optimism of the late 1960s when the then Surgeon General of the United States announced “we can close the book on infectious diseases”? For some years now it has been clear that the situation with respect to the treatment of common bacterial infections, especially in hospitals, is poor, if not dire.1 Physicians have a diminishing armamentarium of antibiotics available...

If we are to continue with the current practices in the treatment of infectious disease, new and reliable sources of novel antimicrobials are badly needed for all types of microbial diseases. Where will they come from? And who will produce them? I take issue with the oft-repeated assertion that it is “hard” to find new compounds with the required therapeutic activity from nature, the assumption being that Big Pharma has exhaustively screened all of the available sources of bioactive compounds and that slim pickings remain. Emerging technological advances make it increasingly clear that this stance is indefensible.

I take issue with the oft-repeated assertion that it is “hard” to find new compounds with the required therapeutic activity from nature.

If we assume that upwards of 100,000 different strains of bacteria and fungi may have been screened for therapeutic agents by the industry,2 this represents but a fraction of the population of the microbial kingdoms (a gram of soil may contain a thousand different bacterial species). There are likely billions of antibiotic-producing strains in the biosphere, each with the potential to produce 10 times this number in terms of bioactive small molecules with drug potential. This information comes from two sources. First, more than 90 percent of microbes cannot be grown under laboratory conditions. This includes all possible environmental sources: marine, terrestrial, endosymbionts, and so on. Second, extensive genome sequencing over the past 10 years has revealed that one of the most productive bacterial sources of antibiotics and other therapeutic agents, the streptomycetes, possess the genetic capacity to make as many as 30 different bioactive small molecules.3 The so-called cryptic biosynthetic pathways are not expressed (or are poorly expressed) under traditional fermentation conditions, and their products have been missed because of inadequate and insensitive screening processes.

This treasure trove of bioactive compounds will not yield its secrets and benefits easily. New methodology must be developed to grow fastidious microbes in the laboratory and creative approaches to the cloning and expression of identified, but product-unknown, biosynthetic pathways must be developed; new expression hosts and pathway expression processes are essential for success. Another major hurdle is the isolation, purification, and structure determination of the compounds produced by the microbial hosts; traditional natural product chemistry is almost a dark art, with very few skilled practitioners worldwide. However, new methods of cell-based screening, compound isolation, and structure determination are coming on the scene; increasingly sensitive instrumentation may resolve other aspects of the discovery problem. There is an excellent model to be found from the revolution in DNA sequencing—it took several billions of dollars to obtain a draft nucleotide sequence of the human genome in 2000; 10 years later we are speaking of $1000 genomes (or less!).4 More important, for low-molecular-weight bioactives, microbial genome sequences will soon be priced at $10 a shot and completed in a day. Antibiotic discovery will start with the complete nucleotide sequence of a biosynthetic pathway for an unknown compound, reversing the traditional approach.

This treasure trove of bioactive compounds will not yield its secrets and benefits easily.

Of course, the identified pathways still have to be converted into products, but prototypes for this type of engineering are already established; even Escherichia coli is considered a good candidate as expression host.5 In addition, the possibility of creating new types of molecules by making hybrid biosynthetic pathways is a field of investigation that will develop in parallel with these approaches.6 Engineering the amino acid components of nonribosomal peptides is yet another method that shows promise for the production of nonnatural molecules in vivo.7

To capitalize on the increasing availability of new classes of small-molecule therapeutics, comparable advances in high-throughput screening and testing of their diverse bioactivities using cell-based assays will be essential; one can predict more extensive use of reliable insect and worm models of human disease.8 Imagine screening thousands of microbial compounds against hundreds of disease syndromes in microtiter plates! Many of the necessary procedures are already in place but they need to be made amenable to high-throughput analysis.

Also needed is a more comprehensive understanding of natural microbial communities and their interactions with their hosts, especially in humans. Studies of the nature of human and animal microbiomes are revealing extensive roles of commensal microbes in the health and maintenance of their complex hosts. Advances in this field will surely reveal unanticipated drug targets for a variety of afflictions.

All of these technological advances—and more, such as systems biology and metabolic network mapping—will contribute to the means of producing newer generations of antimicrobial agents. But who will be responsible for the implementation of these revolutionary developments in the process of drug discovery and development? Big Pharma is too hidebound by the tradition of overmanagement, and “small” biotech is too dependent on venture capital. What is needed is a new drug discovery model—perhaps university research combined with government grant funding. A number of universities around the world have initiated preclinical, preindustry discovery groups with the goal of bridging the freedom and originality of academic research with the hard facts of drug development. This should be the way of the future!

This essay is adapted from F1000 Biology Reports 2010, 2:26 (http://f1000biology.com/reports). See the original paper for a deeper discussion of the proposed technologies, complete reference listings, and links to their faculty evaluations.

Julian Davies is head of faculty of Microbiology at F1000. He is a Fellow of the Royal Societies of the United Kingdom and Canada. He is past president of the American Society of Microbiology and the International Union of Microbiological Societies.

1. B. Spellberg et al., “The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America,” Clin Infect Dis, 46:155–64, 2008. [F1000 Factor 6.0 Must Read, evaluated by Antonio Cassone 15 Jan 2008.]
2. R.H. Baltz, “Marcel Faber Roundtable: is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration?” J Ind Microbiol Biotechnol, 33:507–13, 2006.
3. Y. Ohnishi et al., “Genome sequence of the Streptomycin-producing microorganism Streptomyces griseus IFO 13350,” J Bacteriol, 190:4050–60, 2008.
4. R.F. Service, “Gene sequencing: the race for the $1000 genome,” Science 311:1544–46, 2006.
5. B. Pfeifer et al., “Process and metabolic strategies for improved production of Escherichia coli-derived 6-deoxyerythronolide B,” Appl Envir Microbiol, 68:3287–92, 2002.
6. L.S. Sheehan et al., “Engineering of the spinosyn PKS: directing starter unit incorporation.” J Nat Prod, 69:1702–10, 2002.
7. S. Doekel et al., “Non-ribosomal peptide synthetase module fusions to produce derivatives of daptomycin in Streptomyces roseosporus,” Microbiology,154:2872–80, 2008.
8. T.I. Moy, et al., “High-throughput screen for novel antimicrobials using a whole animal infection model,” ACS Chem Biol, 4:527–33, 2009. [F1000 Factor 6.0 Must Read, evaluated by David Triggle 25 Nov 2009.]

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