Drug discovery

Not as fab as we thought

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Ever since penicillin was isolated from mould, it has been assumed that naturally occurring antibiotics are good starting points for drug-discovery programmes. The latest study shows that this isn't always true.

Drug-resistant bacterial infections continue to occupy the headlines, amid increasingly desperate calls for new antibiotics to treat infectious diseases. Some of the most alarming reports concern 'Gram-positive' pathogens1, which are a pervasive nuisance in both the clinic and the world at large. The recent discovery2 of the potent antibiotic platensimycin was therefore greeted with great enthusiasm. Platensimycin was isolated from soil-dwelling Streptomyces platensis microbes, and represents a new class of antibiotic that acts against Gram-positive pathogens. But on page 83 of this issue, Brinster et al.3 provide a sobering lesson in what drug discoverers call target validation. The authors show that, although compounds that have the same mechanism of action as platensimycin are effective antibacterials in soil, they are inactive in models that simulate environments relevant to infection.

The problem with existing antibiotics is that they attack a narrow spectrum of bacterial physiology: most interfere with the synthesis of bacterial DNA, proteins or cell walls. There is therefore great interest in exploring new biological targets for antibacterial therapies. One potential target is fatty-acid biosynthesis, and the past few years have witnessed intense efforts to identify inhibitors of this process.

Fatty acids are organic molecules that contain long, unbranched hydrocarbon chains of up to 18 carbon atoms. Their biosynthetic machinery is encoded by several genes involving the fab loci of the bacterial genome. Fab proteins come together to construct fatty acids, two carbon atoms at a time, in a cyclic process. The promise of this biosynthetic pathway as an antibacterial target stems from the fact that it is essential for the formation of cellular membranes in a wide range of bacterial pathogens. The process is distinct from fatty-acid biosynthesis in humans, suggesting that antibiotics that block this mechanism could be made that are selectively toxic for bacteria.

Several compounds have already been identified that inhibit specific steps in the bacterial biosynthesis of fatty acids. These include synthetic compounds (such as the antituberculosis compound isoniazid and the general-purpose antibiotic triclosan) and naturally occurring compounds (such as cerulenin and thiolactomycin, both broad-spectrum antibiotics) 4. The synthetic compounds, however, have had only niche applications — isoniazid in combination therapies and triclosan in soaps and plastics — whereas the natural products have never proved useful in the clinic. Nevertheless, the discovery of platensimycin as a new addition to the roster of fatty-acid biosynthesis inhibitors generated renewed excitement about this antibiotic class.

Yet studies dating as far back as the late 1970s have shown that Gram-positive bacteria can acquire fatty acids from their surroundings and incorporate them into their cell membranes5. Given that human serum is a rich source of such acids, these findings seriously undermine the idea that inhibitors of bacterial fatty-acid biosynthesis could fight infections: the effects of such drugs would be overcome if the pathogens simply take up fatty acids from serum. Brinster et al.3 conducted experiments to directly address this contradiction, and present compelling evidence that calls into question the value of antibiotic therapies that target fatty-acid biosynthesis.

The authors began their investigation by treating several clinical isolates of Gram-positive pathogens — including strains resistant to commonly used antibiotics — with triclosan and cerulenin, in growth media that either contained or lacked fatty acids. They found that both inhibitors are quite effective at inhibiting the growth of drug-resistant strains in standard laboratory media (which lack fatty acids), but that this effect was abolished when certain fatty acids were added individually, or when human serum was added. They also observed that the strict requirement for fatty-acid biosynthesis to sustain bacterial growth is superseded when fatty acids are readily available in the growth environment, as demonstrated by the low level of expression of fab genes in bacteria that were cultured under these conditions. Moreover, they found that mutant strains of bacteria that were defective in up to five of the fab genes flourish in fatty-acid-rich serum.

In vitro experiments are all well and good, but the gold-standard studies for drug discovery are those performed in vivo. Most significantly, in animal experiments testing the implications of fatty-acid biosynthesis in host infection, the authors were especially careful to run their tests under conditions that closely reflect real-world infection, a criterion sometimes overlooked in such studies. Together, their results strongly support the conclusion that fatty-acid biosynthesis is a poor target for drugs against Gram-positive pathogens.

This work3 offers a profound lesson in target validation. A cornerstone of modern antibacterial drug discovery is that cellular processes are investigated in vitro (Fig. 1), because this is quicker, cheaper and simpler than investigating these processes in animals. Such in vitro models are usually fine, because the bacterial processes that are important for life in a Petri dish are also almost always essential for the survival of bacteria that have infected a host — although many more bacterial functions that can't be modelled in a dish will also be crucial for infections. But the current study begs the question: what if functions important for growth in the laboratory are superfluous for growth in a host? In raising this point, Brinster and colleagues' work is likely to be regarded as a landmark that will raise the bar for target validation in drug discovery in the future. A likely outcome is that novel biological targets for antibiotics will be scrutinized with many more experiments than before to understand the importance of those targets for infection (rather than just their role in bacterial survival in vitro).

Figure 1: Sure of the cure?
figure1

Antibiotics are usually tested for their efficacy in vitro. Here, the red regions around antibiotic-impregnated wafers indicate areas of poor bacterial growth. Brinster et al.3 show that such assays can be misleading if they don't accurately simulate environments relevant to infection in vivo.

This work also challenges common assumptions associated with the discovery of naturally occurring antibiotics from organisms such as streptomycetes. It is tempting to conclude that the very existence of such compounds validates the target of the antibiotic as being suitable for pharmaceutical intervention. This idea stems from the notion that antibiotics are the result of an evolutionary arms race among soil-dwelling bacteria. But one must be mindful of the environmental conditions that define the limits of this struggle. Antibiotics from streptomycetes have evolved to provide those organisms with an advantage in a soil environment where fatty acids, for example, are in short supply.

Antibiotic drug discovery and development is an onerous process fraught with long development times, high costs and the risk that regulatory agencies will ultimately reject the discoverer's application to sell the fruits of their labours6. Brinster and co-workers' work3 will resonate with those working in drug discovery, and will inspire renewed efforts to understand the basis of bacterial pathogenesis.

References

  1. 1

    Weigel, L. M. et al. Science 302, 1569–1571 (2003).

  2. 2

    Wang, J. et al. Nature 441, 358–361 (2006).

  3. 3

    Brinster, S. et al. Nature 458, 83–86 (2009).

  4. 4

    Heath, R. J., White, S. W. & Rock, C. O. Prog. Lipid Res. 40, 467–497 (2001).

  5. 5

    Altenbern, R. A. Antimicrob. Agents Chemother. 11, 574–576 (1977).

  6. 6

    Fernandes, P. Nature Biotechnol. 24, 1497–1503 (2006).

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