Chemistry issues hinder antibiotic development

A call-to-arms for research into novel antibiotics has reignited the debate concerning how to overcome the barriers to discovering and developing these much-needed treatments.

Business, regulatory and scientific issues all provide disincentives for companies to invest in antibiotic research and development, writes Carl Nathan from Cornell University, New York, in a commentary in Nature (Nature 431, 899–902 (2004)). So, a not-for-profit drug company, encouraged by tax incentives, and staffed by industry professionals and executives on sabbaticals, could potentially address this need.

An important issue, which is often overlooked, is the science underlying the development of novel antibiotics, says Christopher Lipinski, Adjunct Senior Research Fellow at Pfizer Global R&D, and member of the Scientific Advisory Committee for the Global Alliance for Tuberculosis Drug Development.

Alternatives to standard tools and technologies are badly needed. “Combinatorial libraries, so widely used in screening against many non-infectious disease target types, have proved almost totally worthless against infectious disease targets,” says Lipinski.

Antibiotics tend to violate Lipinski's 'Rule-of-5' guidelines: they are often larger, more complex in chemical structure, more hydrophilic and have a higher charge than small-molecule drugs for non-infectious diseases. Many antibiotics can be injected, so they aren't constrained by the limitations that oral drugs face in order to reach their intended target.

But many chemical libraries contain predominantly Rule-of-5-compliant chemicals, says Stevan Projan, Vice President, Biological Technologies at Wyeth Research. “We need more molecular complexity in the compound libraries themselves,” he says.

Traditionally, the major source of antibiotics has been natural products, but for years there has been a decrease in industry investment in this area of research.

Natural-product screening is tedious, and tends to identify many old classes of drugs, says Karen Bush, Biology Team Leader, Antimicrobial Agents Drug Discovery at Johnson & Johnson. “When Discovery programmes are run with tight deadlines, there is sometimes a reluctance to allow for the time lag between initial identification of activity and eventual isolation of sufficient amounts of material to conduct preclinical safety and efficacy testing.”

What's needed are a good natural-products library, especially with novel sources of natural products; analytical chemists to determine novel structures; and medicinal chemists to enhance the activities of natural products to make them act as better drugs, says Projan. “The hard part is finding novel sources and novel natural products,” says Projan. “The others are doable but rarely considered up front by most biotechs embarking on drug discovery programmes.”

“The major issues hampering the development of novel molecules have been in the identification, synthesis and optimization of active natural product 'hits' identified from various biological extracts,” says Peter Tambros, CEO of VivoQuest, a natural-products-based company in Valley Cottage, New York.

Many antibiotics have been made by semisynthetic modifications. Any modification has to not only improve the pharmacokinetics and pharmacodynamics of a drug, but, in the case of antibiotics, it must also try to overcome the problem of antibiotic resistance. As natural products are generally more structurally complex than small-molecule drugs, extensive modifications are tricky and complete synthesis of natural-product-like compounds is challenging.

However, minor modifications of novel natural compounds by semisynthetic methods shouldn't present too much of a problem, says Christopher Walsh, Professor at the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. Usually, chemists pick one or two sites for modification, says Walsh. “From this point of view, many — probably most — of the natural products that are therapeutic candidates will offer one or a few sites for selective modification.”

So, there is the science to turn this crisis around, says Solomon Nwaka, Scientific Officer at the Medicines for Malaria Venture. “With appropriate resources, a clear structural strategy and support from all sectors, this impending gap in availability of antibiotics can be prevented.”

Pooling these talents can only be beneficial, says Nathan. “What we have now is a great deal of expertise in antibiotic development — including first-hand knowledge, earned at great cost, of what does not work — that is being scattered as teams are broken up,” he says. “We need a venue where teams can come back together with a charge to develop antibiotics, and the tools and compounds suited to the task.”