Microbial drug resistance is a real and growing problem, but drugmakers face disincentives: a plethora of products already on the market, the difficulty of differentiating drugs, and the habit of reserving truly new drugs for emergencies. Big Pharmas are backing out, creating opportunities for small companies who feel they can play successfully. But lack of interest from large partners means biotechs can't access the assets those firms hold, so many start-ups are pairing up with peers. Some firms are building businesses around an abundance of targets derived through genomics. But others are deliberately avoiding working with novel genetic code and instead studying whole cells and physiological changes in organisms. Many firms are addressing the lack of chemical diversity against targets. Some of these are pursuing diversity through natural products like marine microbes, insisting they'll fare better than earlier firms did, in part because of technological advances. Others are trying to create diversity synthetically, by taking structural approaches to understanding targets new and old, as well as compounds. Crystallography, in silico libraries, computational models and mass spectroscopy are key tools in iterative development processes that remain unproven in the anti-infectives field. Some firms are seeking to minimize the risks of novelty, by putting their efforts into developing new versions of antibiotics that worked well before resistance grew. No matter what technological approach start-ups take to developing antibiotics, all face similar challenges external to themselves-primarily in regulatory affairs and funding, but also in hunting Big Pharma partnerships.

Xiangmin Cui's vision, in co-founding Pan Pacific Pharmaceuticals two years ago, was to combine his personal knowledge of traditional Chinese medicines with the scientific training he received both in China and at Stanford University. Pan Pacific's lead compound for rheumatoid arthritis has been successfully cloned and expressed, and shown to be identical in structure and activity to a naturally occurring molecule with potency against the disease.

Combine two smaller weak businesses and you get a big weak business, unless the merger brings out hidden assets. Can the latter happen to Upjohn & Pharmacia? Maybe, but the obstacles against it are significant.