Overcoming Bacterial Resistance: Role of β-Lactamase Inhibitors

Resistance to modern antibiotics is currently a major health concern in treating infectious diseases. Abuse, overuse, and misuse of antibiotics in treating human illness have caused the pathogens to develop resistance through a process known as natural selection. The most common mechanism of resistance to β-lactam antibiotics is the production of β-lactamases, which destroy β-lactam antibiotics before they reach the bacterial target. Over the last two decades, combination therapy involving treatment with a β-lactam antibiotic and a β-lactamase inhibitor has become very successful in controlling β-lactamase-mediated bacterial resistance. Currently available inhibitors like clavulanate, sulbactam, and tazobactam are not suitable for use in combination with β-lactamase-susceptible antibiotics against the newly emerged β-lactamases, including class C enzymes. Over the last 10 years, X-ray crystallography, electrospray ionization mass spectrometry, and molecular modeling have become useful tools for determining the molecular basis for interactions between β-lactamases and β-lactamase inhibitors. This chapter describes some of the structure- and mechanism-based approaches that have been utilized in designing new broad-spectrum β-lactamase inhibitors of various β-lactam classes.