Developing New Antibiotics

More than anything else in the world, people die of infectious diseases, and this is especially true for children. In big part, the reason for these high mortality rates is that microbes have become over years increasingly drug resistant. Once routinely treated with prescription antibiotics, disease such as pneumonia, malaria, meningitis, and tuberculosis become fatal because the pathogens are resistant to our arsenal of antibiotics.
But the problem is even bigger than that. In the 1980’s the pharmaceutical companies were developing ~5 antibiotics each year. Today, the average is less than 1. Unfortunately, it is more profitable to make drugs that treat chronic conditions (depression, blood pressure…). This combination leaves us dangerously exposed: the pathogens are more resistant than ever, and we have fewer tools to treat them with.

Developing novel antibiotics:
Our computational screen identified potential inhibitors for BtuCD-F, one of which is shown here docked to the target site on BtuC.
This small molecule, compound MSJSK12 occupies a pocket in BtuC into which BtuF inserts a helical “finger” in order to attach to BtuC. By occupying this pocket, compound MSJSK12 inhibits the association of BtuCD with BtuF, and as a result transport is inhibited.
We are currently employing the same approach to develop inhibitors to transporters that are essential to pathogenesis (BtuCD is not).

Developing new antibiotics

In many pathogens there’s an ABC transport system that is essential to the survival of the pathogen within the host’s environment. For example, in Bacillus anthracis (Anthrax), if a component of an ABC import system for manganese and iron is deleted from the chromosome, Anthrax becomes completely a-virulent. This tight correlation between pathogenicity and a pathogen’s ABC transport systems is also observed in Streptococcus pneumonia, Mycobacterium tuberculosis, Yersinia pestis, Pseudomonas aerogenosa,Salmonella, and other important pathogens.
We aim to develop inhibitors for transport systems that are essential for virulence.
Common to all these systems, is that for transport to occur the transporter must form a productive transport complex with the system’s cognate substrate-binding protein. We will try and inhibit this complex formation.
We have designed a computational in-silico screen to test hundreds of thousands of small molecules for their ability to inhibit the association between BtuCD (the transporter) and BtuF (the substrate-binding protein). We use BtuCDF as a model system to develop our methodology but our approach is readily expandable to any ABC transport system. The computational screen helped us identify ~8000 promising candidates which we began to test experimentally. We have identified several compounds that potently inhibit BtuCDF’s function in-vitro and we are now testing these compounds in-vivo. We truly believe our development may lead to a new class of antibiotics in the future.