Y not an irresistible antibiotic!!

Greetings

    As spoken several times in this post, anti microbial fight has been a loosing war (Link) with science running badly out of options. This is no less agreeable in many cases of hospital acquired infections (which I sometimes prefer to call "healthcare vectored" infections). With the WHO calling us into a possible post antibiotic era (Link) we are desperately looking for options. But a basic question remains in the minds of many people. Is it not possible for us to develop an irresistible antibiotic?

Source: Small things considered. Link

    I'm reminded of a post published in ASM blog (Link) which basically calls up a similar question. The beewolf wasps cultivate Streptomyces bacteria, which defends them from a pathogenic fungus. The question is why hasn't the fungus evolved resistance to these antibiotics. Seems like a fascination. But the simplest point is whenever the resistance has evolved, the wasp has lost the evolutionary advantage leading to selection of those bacterial strains that has protected them from the fungus. Its a simple Red queen hypothesis in action.

   That seems to be explain. But the question is why not make an antibiotic that is absolutely irresistible. To find such a target, it is obvious that the target molecule or structure has to be so conserved that even the slightest change is lethal. That essentially means the organism is trapped from evolving. On one hand evolving resistance is lethal, on the other hand not evolving becomes a target for antibiotic. Think about it for a moment. Such a chemical would be absolutely the golden goose of medicine.

     Mutation as essential as it seems also has a slippery trick in its game. During the course of evolution, if there is an absolutely unchangeable component, they tend to become a conserved sequence. If such a component is of central importance they would be seen across multiple spectra of life. To make an antibiotic against that central component is lethal across the group. If you are to make a chemical that is on a conserved component but not central, a simple evolution will select for the strains without the component since they are accessories. The antibiotic needs to be selective and thus has to attack a component that is distinct enough, which by default means evolvable enough.

  Let me take the example of ATP synthase inhibitor (Link). ATP synthase is a very highly conserved central function enzyme. Mycobacterial ATP synthase can be inhibited by chemical such as bedaquiline. The structure of synthase is different enough from humans (otherwise it would inhibit our ATP synthesis). I said "component is distinct enough, which by default means evolvable enough". The mechanism of action was infact resolved by creating mutants. In other words, even for a chemical as good as attacking the core chemical, resistance was simply possible.

    So that automatically into question where are we going to look for new antibiotics. Of more than any, Penicillin and Streptomyces have probably given us more compounds than anything. Focus has also been on variety of plant extracts which has not yielded much success.

   Let us evoke back the concept of beewolf wasps cultivating Streptomyces bacteria. The core concept is you set a evolutionary race to come up with a better compound everytime resistance sets in. The best candidate that I could think of are normal flora. Normal flora form a part of protection by attacking the invading species. They have an evolutionary requirement to keep up in improved defense. As a proof of concept, I want to cite a article by Valluru etal. The study was able to demonstrate presence of compounds produced by Lactobacillus strains which were better active in acidic conditions.

    It is the view of many that probably over the long run, antibiotics is not an answer. It is also the view, if probiotics can be designed to attack the incoming pathogens it would produce a better outcome, since both have a competing interest. Perhaps in this regard, phages once again seems to be a great answer. 

Perhaps that answers some questions on "Why not a fixed chemical which is a irresistible chemical??"

Dasari, S., Shouri, R., Wudayagiri, R., & Valluru, L. (2014). Antimicrobial activity of Lactobacillus against microbial flora of cervicovaginal infections Asian Pacific Journal of Tropical Disease, 4 (1), 18-24. DOI: 10.1016/S2222-1808(14)60307-8