Tackling the Antibiotic Resistance Caused by Class A β-Lactamases through the Use of β-Lactamase Inhibitory Protein

[Formula: see text]-Lactams are the most widely used and effective antibiotics for the treatment of infectious diseases. Unfortunately, bacteria have developed several mechanisms to combat these therapeutic agents. One of the major resistance mechanisms involves the production of [Formula: see text]-lactamase that hydrolyzes the [Formula: see text]-lactam ring thereby inactivating the drug. To overcome this threat, the small molecule [Formula: see text]-lactamase inhibitors (e.g., clavulanic acid, sulbactam and tazobactam) have been used in combination with [Formula: see text]-lactams for treatment. However, the bacterial resistance to this kind of combination therapy has evolved recently. Therefore, multiple attempts have been made to discover and develop novel broad-spectrum [Formula: see text]-lactamase inhibitors that sufficiently work against [Formula: see text]-lactamase producing bacteria. [Formula: see text]-lactamase inhibitory proteins (BLIPs) (e.g., BLIP, BLIP-I and BLIP-II) are potential inhibitors that have been found from soil bacterium Streptomyces spp. BLIPs bind and inhibit a wide range of class A [Formula: see text]-lactamases from a diverse set of Gram-positive and Gram-negative bacteria, including TEM-1, PC1, SME-1, SHV-1 and KPC-2. To the best of our knowledge, this article represents the first systematic review on [Formula: see text]-lactamase inhibitors with a particular focus on BLIPs and their inherent properties that favorably position them as a source of biologically-inspired drugs to combat antimicrobial resistance. Furthermore, an extensive compilation of binding data from [Formula: see text]-lactamase–BLIP interaction studies is presented herein. Such information help to provide key insights into the origin of interaction that may be useful for rationally guiding future drug design efforts.