Drug delivery approaches to overcome bacterial resistance to β-lactam antibiotics

Abstract

Background: Since its landmark discovery in 1928, penicillin has had a profound impact on the quality of human life. The ability to treat and cure deadly infections and bacterial diseases has forever changed our medical profession and way of life, providing unprecedented relief from pain, suffering, and death due to microbial infection. Penicillin and its many derivatives have dominated the field of antibiotics research and development, while demonstrating unprecedented success as a therapeutic used around the world. The β-lactams, as a family of more than six structural variants all having the 2-azetidinone ring, have worked extremely well against a wide variety of disease-causing pathogens, while exerting little if any toxicity towards mammalian cells. Penicillin has truly been a wonder drug. However, over the last 60 years, drug resistance to the penicillins has steadily been increasing in frequency and severity, to the point where today there are grave concerns that the β-lactams will soon no longer be able to stop deadly bacterial infections. Objective: The aim of this discussion is to present what has been investigated as a means to enhance the performance of β-lactam antibiotics against drug-resistant bacteria, and what is currently being explored or is likely to prove useful in the future. Methods: This review provides a descriptive overview of the various published ways to enhance the clinical effectiveness of β-lactam antibiotics, beginning with the early and ongoing search for more powerful β-lactam derivatives, penicillinase-stable variants, β-lactam prodrugs, intracellular delivery approaches, nanocarrier-based strategies, and new β-lactams with an alternative mechanism of action. Conclusion: Of the progress made so far to develop approaches to overcome bacterial resistance to β-lactams, the use of drug carriers such as liposomes and nanoparticles seems to hold significant promise, as do structural variants that operate through different biological modes of action.

Keywords::

• antibiotic resistance
• β-lactamases
• β-lactams
• drug delivery
• nanoparticles
• penicillin

Acknowledgements

The authors thank the National Institutes of Health (R01 AI51351) and National Science Foundation (NSF 0620572) for funding the research in this area, and also the University of South Florida Office of Technology Development for a Florida High Tech Corridor matching grant.