Prokaryotic pow-wows and tackling antibiotic resistance
Antibiotic resistance is and will continue to be a key issue in the years to come. Many pathogens have been dubbed “super-bugs” as a result of their ability to persist in the presence of multiple antibiotics. Some bacterial pathogens, like totally drug-resistant tuberculosis, MRSA, Klebsiella pneumoniae, and Acinetobacter baumannii are of particular interest because of their clinical prevalence and ability to quickly acquire drug resistance.
One primary concern with antibiotic resistance is the lack of new drug development. The median cost of developing a new drug is $4.2 billion dollars (forbes article), and without proper antibiotic stewardship, a drug may only be useful for 2 or 3 years. That’s not much return on investment. Big pharmaceuticals will not dump money into a drug without the prospect of long term revenue.
However, there are novel ways to tackle the issue of antibiotic resistance without the billion bucks. The most heavily researched mechanism of antibiotic resistance is mediated by a class of enzymes called betalactamases. 80% of the research in the field of antibiotic resistance has been focused on betalactams, and we seem to have forgotten that there are several other classes of antibiotics that we can play with. I discussed the problem of such heavy focus on one antibiotic here: Gripes with antibiotic resistance research.
Bacteria have gained resistance to every class of antibiotics including aminoglycosides, tetracyclines, quinolones, and polymyxins. Each method of resistance is typically granted by an enzyme, and these enzymes should be new drug targets. If we can inhibit an enzyme that grants resistance, then by coupling the new drug with an old antibiotic, we can reutilize obsolete antibiotics.
Another method that has recently gained traction is the inhibition of virulence factors. Most bacteria are not virulent, and incapable of infecting humans. Remember, the human body is an incredibly harsh environment for a microbe. However, those that are virulent typically carry genetic determinants that give them the ability to colonize a host. For example, Escherichia coli is a commensal bacteria of the human gut, but some strains have gained the ability to produce toxins or adhere to particular mucosal surfaces, making these strains virulent. The development of new drugs to inhibit virulence may be able to prevent disease. I briefly described one such method in Dealing with antibiotic resistance through anti-virulence factors, where inhibition of a toxin leads to survival of mice and protection from disease.
One process that can be considered a virulence factor is quorum sensing, a mechanism for bacteria to detect population density. Bacteria excrete peptides that they also have receptors for, and when the concentration of bacteria increases, so too does the excreted peptides. When the population reaches a particular concentration, gene expression changes and may induce virulence factors. Pseudomonas aeruginosa and A. baumannii are opportunistic human pathogens, and through quorum sensing are able to coordinate the formation of biofilms, a virulence trait. Inhibition of the quorum sensing may inhibit the progression of disease, and a method for discovering drugs that can inhibit this system is described in this paper published this month in PNAS: A high-throughput screen for quorum-sensing inhibitors that target acyl-homoserine lactone synthases.
The growing issue of antibiotic resistance is critical to global health, but the problem is still just a pea under a mattress and not enough attention has turned its way. Translational research and drug development are absolutely integral to advancements in the biomedical sciences, but basic research will give insight to novel drug targets and molecular mechanisms that we can utilize to cure disease. The pre-antibiotic era and the days where a common strep-throat or UTI would kill you are gone. However, without progress in research, stewardship, and activism, we could certainly regress.