Dual targeting antimicrobials and the circumvention of resistance

In summary

Since the 1990s, City St George’s researchers have made seminal contributions in understanding how dual-targeting antibiotics can prevent the emergence of resistance in serious bacterial infections.

Their work has led to the global approval and clinical success of gemifloxacin and besifloxacin, offering more effective treatment options for pneumonia and bacterial conjunctivitis.

What did we explore and how?

The research, led by Professor Mark Fisher and colleagues, focused on Streptococcus pneumoniae, a gram-positive bacterium responsible for pneumonia and other infections, including meningitis.

Although typically sensitive to penicillin, resistance has been increasing, prompting the need for alternatives.

Fisher’s team explored quinolones - synthetic antibiotics that block bacterial DNA replication by targeting specific enzymes.

Their findings demonstrated that dual targeting - inhibiting two bacterial enzymes simultaneously can significantly reduce the likelihood of resistance developing.

They worked with SmithKlineBeecham to determine the mode of action of gemifloxacin (Factive), showing it met the criteria for dual targeting.

This evidence was instrumental in securing FDA approval for the drug, particularly for treating infections caused by penicillin-resistant and multidrug-resistant S. pneumoniae.

Later, they also investigated besifloxacin, a fluoroquinolone developed by Bausch and Lomb.

In 2008, the team clarified its mode of action, leading to FDA approval in 2009 and an expanded licence in 2012 to include virulent pathogens like Pseudomonas aeruginosa.

Benefits and influence of this research

This research has directly influenced the design and licensing of next-generation antibiotics.

Without the detailed molecular insights from Fisher’s group, pharmaceutical efforts would rely heavily on less efficient trial-and-error approaches.

• Gemifloxacin is now marketed globally, and its dual action is cited in pharmaceutical marketing. It remains a frontline treatment for drug-resistant pneumococcal infections, achieving sales of $5.1 million (2010) and $6.3 million (2011) in the US.
• Besifloxacin has become a leading treatment for bacterial conjunctivitis, shown to work faster and more effectively than alternatives. Between 2010 and 2012, 400,000 prescriptions were filled in the US. InSite Vision recorded $1.2 million in royalties in 2011 and $2.1 million in 2012.

These drugs are now essential tools in the global fight against antibiotic-resistant infections.