Lactamase contributes to antibiotic resistance by inactivating a major class of antibiotics. The presence and diversity of these bacterial enzymes complicate the treatment of bacterial infections. Understanding lactamase is important for global public health, as it relates to the problem of drug-resistant bacteria.
Understanding Lactamase
Lactamase is an enzyme produced by bacteria that can break down certain antibiotics. Penicillin’s discovery in the 1920s revolutionized bacterial infection treatment. However, bacteria quickly evolved defenses; penicillinase, the first penicillin-destroying enzyme, was identified in the 1940s.
There are numerous types of lactamases, which vary in their structure and the range of antibiotics they can inactivate. Some types, like extended-spectrum beta-lactamases (ESBLs), can break down a broader range of antibiotics compared to earlier forms.
The Mechanism of Action
Lactamase enzymes work by targeting a specific chemical structure found in many common antibiotics: the beta-lactam ring. This ring is a four-atom structure that is integral to the antibiotic’s ability to kill bacteria. The enzyme acts like a molecular scissor, performing a hydrolysis reaction that breaks open this beta-lactam ring.
Once the lactamase enzyme has opened the beta-lactam ring, the antibiotic molecule is structurally altered and loses its antibacterial properties. This inactivation prevents the antibiotic from interfering with bacterial cell wall synthesis, its primary mode of action. The broken antibiotic can no longer bind to its targets within the bacterial cell, allowing bacteria to continue growing and multiplying.
Lactamase and Antibiotic Resistance
Lactamase enzymes lead to antibiotic resistance. Major classes of beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, are vulnerable to inactivation by these enzymes. For instance, extended-spectrum beta-lactamases (ESBLs) can hydrolyze extended-spectrum cephalosporins, rendering them ineffective. Carbapenemases, a type of lactamase, can inactivate carbapenems, which are often considered last-resort antibiotics for severe infections.
When bacteria produce lactamase, these drugs become ineffective, allowing resistant infections to persist and spread. This resistance has public health implications, contributing to longer hospital stays, increased treatment costs, and higher mortality rates. For example, between 1990 and 2021, antimicrobial resistance, often driven by lactamase production, was associated with 4.71 million deaths globally. The challenge is particularly acute with Gram-negative bacteria, where lactamase production is a primary mechanism of resistance.
Strategies Against Lactamase
Scientists and medical professionals are developing strategies to overcome lactamase-mediated resistance. One approach involves the development of beta-lactamase inhibitors, compounds designed to protect beta-lactam antibiotics from enzymatic degradation. These inhibitors, such as clavulanic acid, sulbactam, and tazobactam, work by binding to the lactamase enzyme, shielding the antibiotic and allowing it to remain active. Newer inhibitors like avibactam, relebactam, and vaborbactam have broader activity against a wider range of lactamases, including some carbapenemases.
Another strategy focuses on the discovery and development of new classes of antibiotics that are not susceptible to existing lactamases. Researchers are exploring novel chemical structures and mechanisms of action to bypass bacterial resistance mechanisms. This involves identifying compounds that can target bacterial processes not affected by lactamase enzymes. The continuous evolution of lactamases necessitates ongoing research into novel antimicrobial agents.
Antibiotic stewardship is an important strategy to combat resistance. This involves the responsible use of antibiotics to slow the emergence and spread of resistant bacteria. Proper stewardship includes prescribing antibiotics only when necessary, selecting the most appropriate drug and dosage, and ensuring patients complete their full course of treatment. By reducing the selective pressure on bacteria, stewardship programs aim to preserve the effectiveness of current and future antibiotics.