Scientists from the University of Bath and University of Cape Town have made an unexpected discovery that could revolutionize hypertension treatment: the commonly-used antibiotic ciprofloxacin blocks the angiotensin-converting enzyme (ACE) through a completely novel mechanism, potentially paving the way for safer cardiovascular medications.
The international research team, led by Professor Ravi Acharya from the University of Bath and Professor Ed Sturrock from the University of Cape Town's Institute of Infectious Disease and Molecular Medicine, found that ciprofloxacin inhibits ACE in a fundamentally different way than existing ACE inhibitors, offering new possibilities for drug design with potentially fewer side effects.
Novel Allosteric Inhibition Mechanism
Unlike traditional ACE inhibitors that bind to the enzyme's active site, ciprofloxacin operates through an allosteric mechanism, binding selectively to a different site in the C-domain of the ACE enzyme. This binding blocks angiotensin I from attaching to the enzyme but crucially does not inhibit ACE's other physiological functions.
"Our study brings a fresh twist by identifying the antibiotic ciprofloxacin as an allosteric inhibitor of ACE - instead of latching onto the active site like traditional inhibitors, ciprofloxacin cleverly binds to an exosite within the C-domain, away from the catalytic pocket," explained Professor Acharya.
The ACE enzyme consists of two parts - the N-domain and C-domain - each harboring an active site pocket. Current ACE inhibitors work by filling these pockets, completely stopping the enzyme's function. However, this approach affects multiple bodily processes because ACE is involved in various chemical reactions affecting kidney function, reproduction, and immune response.
Addressing Current Treatment Limitations
Around one in three adults in the UK suffer from high blood pressure, with approximately 12 million people taking ACE inhibitor medications. While these drugs effectively reduce blood pressure by preventing ACE from converting angiotensin I into the blood vessel-constricting angiotensin II, their broad inhibition of ACE function causes unwanted side effects including persistent coughing and swelling of the throat and tongue.
The "promiscuity" of current ACE inhibitors - their tendency to affect multiple bodily processes - has long been a challenge in cardiovascular medicine. The selective binding mechanism demonstrated by ciprofloxacin could address this limitation by targeting only the blood pressure regulation function while leaving other ACE activities intact.
Research Methodology and Findings
The study, published in ACS Bio & Med Chem Au and funded by the UKRI-BBSRC (Biotechnology and Biological Sciences Research Council), combined expertise from both institutions. Dr. Vinasha Ramasamy and Professor Ed Sturrock from the University of Cape Town investigated the enzyme reaction kinetics of ACE, while Dr. Kyle Gregory and Professor Ravi Acharya from the University of Bath determined the 3D molecular structure of ACE using X-ray crystallography techniques.
The research represents the culmination of a 30-year collaboration between the Acharya and Sturrock research groups, bringing together biochemists with complementary expertise in enzyme structure and function.
Future Drug Development Potential
While ciprofloxacin itself binds too weakly to ACE to be effective as a cardiovascular treatment, the researchers view it as a valuable template for developing a new family of drugs. The team plans to screen different chemical analogues of ciprofloxacin to optimize binding strength and specificity for this new class of inhibitors.
"This groundbreaking research not only advances our understanding of ACE regulation but also highlights the potential for creating next-generation inhibitors that are safer and more efficient in managing hypertension and cardiovascular disorders," said Professor Acharya.
The discovery opens possibilities for developing more targeted ACE inhibitors that could maintain therapeutic efficacy while reducing the side effect burden that affects millions of patients worldwide taking current cardiovascular medications.
