Development of β-Lactamase Inhibitors
The antibiotic adjuvant approach provides alternative and complementary strategies for the discovery of new antibiotics. Adjuvants re-infuse the antibiotic agent to be effective against the resistant strain of interest. The most successful adjuvants in clinical practice today are β-lactamase inhibitors and have proven their robustness and value in past treatments. In this era of increasing antibiotic resistance, we must continue to explore new strategies to combat the different resistant superbugs that are emerging.
Ace Therapeutics offers development services for antibiotic adjuvant β-lactamase inhibitors, which are effective in targeting resistant bacteria by directly targeting resistance or otherwise enhancing the activity of β-lactam containing antibiotics.
Inhibitors of Active Resistance: β-Lactamase Inhibitors
β-lactamases are widely present in bacterial pathogens and are usually obtained by horizontal gene transfer. β-lactamases can hydrolyze and inactivate penicillins, cephalosporins, and carbapenems through ring-opening mechanisms. Clavulanic acid, a natural product containing β-lactam, has poor antibiotic activity, but it showed effective and irreversible inactivation of Ser-β-lactamase (SBLs). This discovery led to the application of the first antibiotic adjuvant. The success of clavulanic acid led to efforts to develop other β-lactamase inhibitors, including various inhibitors paired with penicillin and cephalosporins.
Fig. 1 β-lactamases inhibitors. (Wright G D, 2016)
Development Services of β-Lactamase Inhibitors
β-lactamase inhibitors inhibit the β-lactamases that inactivate widely used β-lactam antibiotics. We provide development services for β-lactamase inhibitors paired with antibiotics including penicillins, cephalosporins, carbapenems, monolactams, etc., designing inhibitors and their selective targeting for different types of β-lactamases.
Targeting SBLs
For drug-resistant bacteria that produce A/C/D SBL, we offer inhibitor development strategies that work primarily through covalent and non-covalent inhibition. Based on covalent inhibition, we offer development services that include diazabicyclooctane (DBO) analogs containing five-membered cycloureas, boronic acid transition state inhibitors (BATSI), and other types. Based on non-covalent inhibition, we can provide development directions such as compounds based on tetrazole.
Targeting metallo-β-lactamases (MBLs)
For B1/B2/B3 MBL, we offer inhibitor development strategies mainly through active-site metal chelation and metal deprivation effects. We can provide development of thiol-containing compounds, nitrogenous aromatic carboxylic acids, sulfonamides, triazole heterocyclic compounds, and other chemical types of inhibitors.
Targeting SBL and MBL
The co-production of MBL and SBL in drug-resistant bacteria is a major clinical problem currently faced. Therefore, the development of inhibitors that dual-target SBL and MBL is desirable. We currently offer the development of inhibitors of types including boronate inhibitors, phosphonates, tetrazoles, β-lactam analogs, etc.
What We Can Offer
The development of inhibitors effective against β-lactamase-mediated resistance has been extensively developed in recent years with a variety of promising chemical types. We offer inhibitor development services for this research area.
- Provide inhibitor compound lead discovery and structure optimization strategies.
- Provide valuable information for optimizing existing chemotypes and developing novel inhibitor chemical scaffolds.
- Provide protocols to study the pharmacokinetic and pharmacodynamic properties between antibiotics and antibiotic adjuvants.
Combination therapy with antibiotics and β-lactamase inhibitors is an excellent strategy for the treatment of superbug infections, and work in this area is constantly evolving. If you would like to learn more about the services for antibiotic adjuvant development, please contact us to help you.
Reference
- Wright G D. Antibiotic adjuvants: rescuing antibiotics from resistance. Trends in microbiology, 2016, 24(11): 862-871.