Discovering a Novel Therapy for Urinary Tract Infections Through Outsourcing In-silico Drug Discovery

This blog post was adapted from an article published on

Antimicrobial therapies are one of the great scientific achievements of the 20th century. For centuries, bacterial infections were deadly, with infamous diseases such as tuberculosis and the bubonic plague seemingly unstoppable. In the 1940s, scientists turned the table on these invisible killers with the discovery of penicillin, the first antibiotic. Viral, fungal, and parasitic infections are also now treatable with small molecule antimicrobial therapies obtained from a local pharmacy.

Although it may seem as if we’ve turned our back on the days in which minor infections were deadly, antimicrobial resistance has become a global health threat. This phenomenon occurs when bacteria, viruses, fungi, and parasites adapt over time and no longer respond to antimicrobial therapies, which increases the risk of disease spread, severe illness, and death. Bacteria can form protective physical barriers or biofilms against antibiotic therapies, a process known as structural antimicrobial resistance, which is often associated with relapse following treatment and is particularly prevalent in urinary tract infection (UTI) patients.

One possible solution to antimicrobial resistance is combining existing antimicrobial therapies with adjuvants. For example, co-amoxiclav, a combination of amoxicillin and clavulanic acid, is widely used today; clavulanic acid inhibits beta-lactamase, an enzyme produced by amoxicillin-resistant bacteria. Similarly, could we combine antibiotics with an adjuvant that breaks down biofilms to specifically address structural antimicrobial resistance?

This idea inspired a collaborative project between the Summers research group at the University of Cambridge and computational chemists from Cresset Discovery (Figure 1). Tryptophanase was found to be essential in biofilm formation, which provided a target for small molecule adjuvant therapies. Subsequently, nine biofilm inhibitors or “hits” were identified to be effective against clinical isolates of pathogenic bacteria associated with UTIs, and displayed no cytotoxicity.

Hit identification

Figure 1: An overview of the research conducted by the Summers group and Cresset Discovery.

In silico drug screening methods offer several advantages over standard in vivo and in vitro assays and were the driving force behind the collaboration. Screening millions of potential drug candidates is extremely time consuming and costly in a wet lab; in contrast, computational methods can offer similar conclusions in a much shorter timeframe and at a fraction of the cost. Cresset’s task was to identify molecules that were likely to show good activity against tryptophanase, could easily enter the bacterial cell, and exhibited low toxicity.

Check out this article on to learn more about antimicrobial resistance, as well as how Cresset Discovery discovered candidate compounds against tryptophanase!