There was a time before antibiotics when infectious diseases were a major killer in industrialized countries. Thanks to antibiotics this is a thing of the past, but is it also a part of the future? The growing prominence of antibiotic resistance suggests this could be the case.
Only a century ago, infectious diseases like pneumonia, influenza, diphtheria, gastrointestinal infections, and tuberculosis made up over half of the deaths in the United States. Since then we have made great strides to combat microbial pathogens namely through vaccinations, antibiotics, and improved hygiene, and now, we live in a time when chronic diseases like cancer and heart disease cause the majority of deaths in the industrialized world.
But how long will this last? With increasing microbial resistance to the drugs that were once considered “breakthroughs,” how long will our drugs be able to keep infectious disease at bay? What will happen when they no longer work? Will we see another pandemic in our time? Will we see many?
Questions like this keep me up at night.
In the past 25 years, humans have produced perhaps one generation, while microbes like E. coli have produced over 50,000 generations. This short generation time allows us to essentially watch microbial evolution in real time.
For example, say you grew a strain of bacteria that could not metabolize a nutrient on agar plates with increasing levels of that nutrient over time. After some amount of generations, you will find that some bacteria will have gained the ability to metabolize the nutrient. Similarly, if you grew a strain of bacteria that were sensitive to an antibiotic on an agar plate containing an antibiotic concentration below that which is toxic to the bacteria, within generations, you could find mutants that are resistant to the antibiotic.
It is this ability to evolve relatively quickly that poses the greatest problem in antibiotic design. Now, instead of simply targeting a pathogen, drugs must be designed to resist the development of resistance, a task that is far more easily said that done.
Current drugs tend to work in a way of direct killing such as such as penicillin that blocks the cross-linking of parts of the cell wall. Others simply limit the growth of bacteria such as by interfering with bacterial protein production, DNA replication, or another aspect of cellular metabolism. As we look to the new generation of antibiotics, some new mechanisms have been suggested:
It is the latter of these two that a group of University of Illinois chemists have shown contributes to the success of a new tuberculosis drug and its analogues.
In February 2014, Li et al. reported in the Journal of Medicinal Chemistry that SQ109, a drug currently in clinical trials to treat tuberculosis, has targets beyond the transporter MmpL3 that plays a role in cell wall biosynthesis that was originally reported. They found that it targets two parts of the production of menaquinone, which is involved in metabolism as well as uncouples the cell membrane by destroying the proton motive force and increasing the membrane permeability. These targets are indicated in the figure below.
They tested this drug and its analogues in many microbial strains beyond the intended M. tuberculosis including Methicillin-Resistant Staphylococcus Aureus (MRSA) and found it to be efficacious in many kinds of bacteria as well as fungi and parasites but not humans. This suggests that the drug and its analogues could potentially used to fight off a great number of infections without harming humans
Most importantly, no instances of resistance have yet been reported.
This study strengthens the argument for having multiple pharmaceutical targets for antibiotics. As populations adapt to the onslaught of therapeutics threatening their species, they become a further heterogeneous population suggesting that a heterogeneous population of pharmaceutical targets are required for efficacious treatment. In further development of antibiotics, it is important to keep this in mind.
Perhaps some day new antibiotics developed with these ideas in mind will allow me to rest easy at night.
Figure: Reprinted with permission from Li, K. et. al, Multitarget Drug Discovery for Tuberculosis and Other Infectious Diseases. Copyright 2014 American Chemical Society.
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