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.

Start-ups bent on determining the 3D structures of proteins are trying to figure out the best ways to package their capabilities and data for sale to drugmakers. Growing numbers of commercial and academic researchers are seeking information about proteins--in particular structural information that influences how these important actors of the body function, and how drugs may fit them. X-ray crystallography is the gold-standard way of getting structural information, and a number of start-ups are gearing up to use the method on a larger scale than ever before. They want to sell the data to drugmakers to use in drug discovery, or better yet, form alliances to obtain and leverage the data-whose value in quantity is as yet unproven. Business models are still evolving: early plans to create databases are fading as firms acknowledge it will take time to accumulate quantities of structures and drugmakers already deluged with data demand actionable information. Service models may suffice temporarily, but won't provide much return in the long-term. Small start-ups are focusing on determining structures of known targets, or new but simple ones, while other better-capitalized companies lay bigger plans: encouraging drugmakers to look at unknown targets and learn more broadly, or to utilize multiple crystals. All the firms are getting involved in screening as a means of lead discovery. Companies starting up in the field of structure-based drug design are competing in the marketplace not only with each other, but against the availability of public data, and other crystal-free methods of gaining information about proteins.