Short answer: The low-hanging fruit has all been picked. For that matter, so has the medium-hanging fruit, and much of the very highest fruit as well.
It's worth taking a minute to review just how most antibiotics have been discovered and developed. Nearly all human pathogens (Mycobacterium tuberculosis is an exception) grow readily in flasks and Petri dishes. This growth typically takes a day or two to cover a plate and can be easily detected by simple inspection.
Spread Staph aureus on a plate and put a drop of some test compound on the plate. Come back the next day, and if your drop has killed the bacteria, there will be a clear spot. Congratulations, you have discovered an antibiotic, and possibly a drug lead compound.
This is how the first antibiotic compounds, such as sulfonamide, penicillin and streptomycin were discovered. Modern methods of screening are much faster and more sophisticated, but rely on the same principle - expose bacteria to a compound and see if they stop growing or are killed.
Of course lots of things kill bacteria but aren't useful drugs - they are toxic, or are poorly absorbed. Medicinal chemists address these problems by adding various chemical groups to a lead compound and repeating the testing process until they find a derivative of the original compound that works as desired.
Pharma companies got very good at this in the 50s, 60s and 70s, and are even better at it today. Even though resistance began appearing almost immediately, there was a robust pipeline of new antibiotics that would keep working when the old ones would not.
So why aren't we finding new antibiotics at a rate that keeps up with resistance anymore? Well, think about all the criteria that a useful antibiotic has to fulfill: it must kill, or at least stop the growth of pathogenic bacteria; it must have high potency so that only a small amount of drug is needed; it preferably is water-soluble and absorbed through the digestive system; it persists for several hours once absorbed and is not rapidly cleared or degraded by the liver and kidney; and neither it nor its breakdown products are toxic to humans.
Bacteria and humans share the same basic biochemistry: we use oxygen to burn sugar to create energy in the same way; our DNA encodes and expresses genes in very similar ways; and we replicate our DNA in very similar ways. One of the biggest differences between humans and bacteria is that they have a cell wall and we don't.
There are thus a finite number of differences between bacteria and humans; only so many biochemical candidates for antibiotic targets. Pharma companies have been working on them for decades now, investing many millions in the effort. More importantly, soil fungi (whose biochemistry is more similar to humans than it is to bacteria) have been at work on this problem for billions of years. They are in a never-ending worldwide effort to find compounds that will stop the growth of bacteria, and thus give them an advantage in the contest for life.
The really good solutions that they found enabled them to grow more and thus become widespread. That's why most good antibiotics in the soil are not hard to find, but easy - they helped fungi to be successful.
This is why the best antibiotics were discovered first, with penicillin being the prime example. The class of drugs to which it belongs - the beta-lactams - are still among the most effective and best-tolerated antibiotics. They target the bacterial cell wall, and thus are targeted at a bacterial feature that has no human counterpart.
The likelihood of finding a new class of antibiotics that is as good as the beta-lactams is zero. New antibiotics will be much more narrowly targeted, preferably toward biochemical pathways that are found only in certain groups of pathogens. Because this approach requires a substantial R&D effort, pharma companies will only make the effort if the financial incentives and the regulatory environment are right. Until then, we can't expect to see much progress.
Posted with Blogsy
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