Drugs for bad bugs: confronting the challenges of antibacterial discovery

20 years to new broad-spectrum antibiotic

Many thanks to Jim Caryl for referencing this remarkable paper [PDF] by David J. Payne, Michael N. Gwynn, David J. Holmes and David L. Pompliano, which describes the actual experience of a major-budget new antibiotic development effort at GlaxoSmithKline. Techno-futurist-optimists like Seekerblog get excited about the promise of molecular biology, in part because we don’t understand how hard it is.

Following are the abstract, introduction and the concluding paragraphs:

Abstract: The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline’s antibacterials strategy going forward.

Introduction: Antibiotic discovery is not very fashionable these days, and yet resistance has evolved to every antibiotic ever placed into clinical practice, irrespective of the chemical class or molecular target of the drug. Despite various bacterial threats to public health (multiply drug-resistant strains, emerging pathogens and biothreat organisms), most large pharmaceutical companies and many biotechnology companies have left the area. Many factors contributed to this exodus, but the fact remains that a better return on investment can be made in other disease areas (at least based on commercial analysis and forecasting). Doubtless the strict regulatory requirements and the competitive commercial environment figures prominently in the calculus, especially for public companies that have responsibilities to shareholders1–8. What might be less well appreciated is just how difficult it is technically, and how much time it takes (according to statistics from the Centers for Medicines Research; see Further information), to make a novel antibiotic (FIG. 1). Converting an early chemical prospect into a medicine that can be used in people is a profound scientific challenge, the difficulties of which are not going to be mitigated by a change in the commercial landscape or public policy. The corporate withdrawal has not only forsaken the antibacterial pipeline but has also greatly diminished the overall capability to generate novel antibacterials. The current portfolio of compounds in clinical trials consists largely of derivatives of chemical classes for which there are already underlying resistance mechanisms — hardly the pharmaceutical firepower needed to face bacteria that are evolving on a timescale of hours. Although the emergence of resistant strains is unpredictable, it is inevitable, and we must be prepared. Excluding the resistance-mediated decline in efficacy, current antibiotics have side effects, difficulties with dosing regimens and restrictions on use, particularly for children, that constrain their utility. There is still a great need and commercial opportunity, for novel antibacterials.

By the mid-1990s, there was little enthusiasm for making yet another incremental improvement to a β-lactam, macrolide or quinolone. Then, in 1995, the determination of the complete DNA sequence of a bacterial genome from Haemophilus influenzae changed everything. The prospect of hundreds of new genes to explore as possible targets sparked new interest in antibacterial discovery and fired the imagination. Embracing the genomics approach, GlaxoSmithKline (GSK) spent 7 years (1995–2001) evaluating more than 300 genes for their potential as targets for novel antibacterials and showing genetically that more than 160 of them are essential. In total, 70 high-throughput screening (HTS) campaigns of individual targets, complete macromolecular biosynthetic pathways and whole-cell screens were run against our synthetic chemical collection at that time. Our aim was to find a novel antibacterial compound that had either Gram-positive or broad-spectrum activity. Now it is time to take stock of what was achieved, to understand what our experience taught us about the antibacterial discovery process and to explain how those lessons influenced our strategy to develop novel antibiotics.

Perspectives on antibacterial research

FIGURE 1 illustrates the timescale and probability of success for each step of antibacterial development using a combination of GSK and industry averages. Industry data illustrate that, on average, 16 Phase I starts are required for one antibacterial product. There are no more than two to three novel-mechanism systemic antibiotics in Phase I studies, and these are Gram-positive-spectrum agents or community respiratory-tract infection drugs. According to these metrics, an additional 12 Phase I starts are needed — a fourfold increase in investment — between now and 2008 to generate one novel-mechanism antibacterial by 2012.

The scenario for the tougher Gram-negative hospital pathogens is more worrisome5. Efflux-mediated resistance, which vitiates the activity of a broad range of structural classes, is formidable in Gram-negative bacteria. Right now, there are no novel MOA antibacterials in Phase I, nor are there even good preclinical leads with promising Gram-negative activity. Assuming aggressive timelines of 3–5 years to deliver a development candidate and 6 years to compete clinical testing, agents for Gram-negative infections could be 9–11 years away (FIG. 1). Taking the attrition into account, it could be as long as 10–15 years before we see a novel mechanism agent for treating Gram-negative hospital infections.

Attrition metrics suggest that the current industry pipeline has a low probability of delivering a single novel-mechanism antibiotic. Companies that remain committed to this area, such as GSK, will need to continuously introduce development candidates into the clinic until (at least) one crosses the finish line as a registered medicine. However, to assure ourselves that novel-mechanism antibiotics will be available for public health, substantially more compounds need to be produced and tested in human studies. This is not going to happen until more drug hunters, both in academia and at companies, engage and apply greater investment to the area.

Concluding remarks

The goal of this review was to focus specifically on the scientific challenges of antibacterial research from the GSK perspective. Some of the challenges encountered were part of a learning curve, and a function of incomplete knowledge at the time. However, many more of the technical difficulties still remain, such as acquisition of biologically relevant chemical diversity, and achieving activity across a diverse spectrum of pathogens, including highly challenging Gram-negative pathogens, with safe drugs. Improvements in the success rate for molecular target HTS will be needed before this is a robust discovery platform for antibacterials. In the meantime, at GSK we have concentrated our effort on lead optimization of novel lead classes from alternative sources. We are mindful of other environmental factors but, from our perspective and as emphasized in this review, the scientific challenges of delivering novel mechanism antibiotics are equally difficult. The painful reality of drug discovery is that things go wrong. This is reflected in the low probability of success for creating an antibacterial worthy of approval for clinical use. The pipeline of novel-mechanism antibacterials is still empty and will remain that way for a considerable time. In conclusion, our experience suggests that synthesizing novel chemical structures that interact with and block established targets in new ways is a robust strategy.