Beta Lactamase Mechanism
Beta lactam antibiotics, like cephams and penicillin derivatives, have a four-member cyclic amide ring that inhibits the peptidoglycan layer synthesis in bacteria. A woven complex of sugar and protein pieces, these first-class bactericidal drugs destroy the integrity of the peptidoglycan layer. This method of bacterial cellular death is especially effective to Gram-positive bacteria due to the peptidoglycan layer providing the outermost resistance to the encapsulated bacterial innards.
Bacteria cells undergo binary fission for asexual reproduction. The bacteria cell furrows to form a cell plate comprising of the cell wall and, consequently, the peptidoglycan layer as the cell divides into two daughter cells. Relying on penicillin-binding proteins to facilitate the synthesis of the new cell wall, this process is also called transpeptidation.
Beta lactam antibiotics are similar in structure to that of the terminal amino acid residues of the small proteins comprising the peptidoglycan matrix, and thus, act as an antagonistic drug by binding to the active site. The nature of the binding between beta lactam antibiotics and the penicillin-binding protein active sites are both irreversible and inhibitory, disrupting the formation of the peptidoglycan layer. This inhibition causes the cell to shed its cell wall, forming a spheroplast that is fragile to its environment and successfully interrupts the binary fission process.
Various strains of bacteria have now developed a form of resistance to beta lactam antibiotics. Beta lactamase hydrolyzes the beta lactam ring, which characterizes beta lactam antibiotics, adding a hydroxyl group to the structure. By adding the hydroxyl group, the beta lactam ring’s structure is destroyed, and the antibiotic is rendered useless. The gene expression for beta lactamase may be induced by repeated exposure to beta lactam antibiotics, increasing the selective pressure for bacteria to obtain the enzyme.
Fighting increased bacterial antibiotic resistance
In order to combat bacterial antibiotic resistance, beta lactam antibiotics can be administered with beta lactamase inhibitors such as Augmentin. It is an antibiotic comprised of amoxicillin (found within the beta lactam antibiotic family) and clavulanic acid. Clavulanic acid acts by using its structure, of which is analogous to beta lactam molecules, as a site for beta lactamase to bind to instead of the beta lactam ring located on the antibiotic. This lets beta lactamase hydrolyze the beta lactam ring in clavulanic acid, keeping the integrity of the beta lactam antibiotic’s structure and allowing beta lactam antibiotics to inhibit peptidoglycan synthesis. Carbapenems also inhibit Class A beta lactamase enzymes through hydrolysis, and are very effective against extended spectrum beta lactamases.
Beta Lactamase Applications
Beta lactamase is especially effective in body fluids and thus have 2 main applications in clinical laboratory settings: diagnosing bacterial infections by preparing a blood culture and Aminoglycoside Antibiotic Assays. Beta lactamase is also noted as a potential novel anticancer chemotherapeutic drug.
Antibiotic discovery is one of the most groundbreaking revelations in medical history. A plethora of diseases such as bacterial meningitis, pneumonia, and septicemia, are curable via antibiotic treatment. The effectiveness of antibiotics, as well as their ability to be tolerated well by patients with low toxicity levels, makes the field of antibiotics a target for drug discovery research. Beta lactam antibiotics such as pencillin, penems, and cephalosporins contain a rigid bicyclic ring structure which functions as a means of bacterial cellular wall synthesis inhibition, causing bacterial death. In addition to the bactericidal function antibiotics possess, recent research has revealed another function: the ability to inhibit tumor cell growth. Currently, there are a multitude of anti-tumor antibiotics utilized in cancer therapy. Tumor growth inhibition occurs via DNA intercalation. Beta lactams have successfully aided chemotherapy delivery directly to tumor sites as well.
A novel class of N-thiolated monobactams, substances of which contain a monocyclic ring instead of the bicyclic ring found in traditional beta lactam antibiotics, has been recently found to induce apoptosis in a specific manner in many tumor cell lines. 4-aklylidene beta lactam antibiotics have been found to be capable of inhibiting matrix metalloproteinases and leukocyte elactase activity. Further research on the potential development and application of beta lactam antibiotics in cancer research has a promising future.
Antibiotics Currently in Clinical Development
Thanks to Pew trusts, this report of antibiotics in clinical development was compiled. As of March 2016, an estimated 37 new antibiotics are in clinical development for the U.S. market to treat serious bacterial infections. Clinical drug development success rate is low. Historical data shows that typically only 1 in 5 infectious disease products that enter human testing (phase 1 clinical trials) will be approved for patients. Below is a look at the current antibiotic pipeline, based on publicly available information and informed by an external expert of Pew. It will be updated periodically, as products advance or are confirmed to drop out of development. Since this list is updated periodically, footnote numbers may not be sequential.
|Drug Name||Development Phase||Company||Drug Class||Expected activity against resistant Gram-negative ESKAPE pathogens?||Expected activity against a CDC urgent threat pathogen?||Potential Indications|
|Zidebactam+Cefepime (WCK 5222)15||Phase 1||Wockhardt Ltd.||Novel beta-lactamase inhibitor+beta-lactam||Possibly||Possibly||Complicated urinary tract infections,6hospital-acquired bacterial pneumonia/ ventilator-associated bacterial pneumonia6|
|OP0595 (RG6080)||Phase 110||Meiji Seika Pharma Co. Ltd./Fedora Pharmaceuticals Inc. (Roche licensee)||Beta-lactamase inhibitor||Possibly||Possibly||Bacterial infections|
|Ceftaroline+Avibactam||Phase 2||AstraZeneca PLC/ Allergan PLC (formerly Actavis)||Cephalosporin+novel beta-lactamase inhibitor||Yes||Yes||Bacterial infections|
|Aztreonam+Avibactam7(ATM-AVI)||Phase 210||AstraZeneca PLC/ Allergan PLC (formerly Actavis)||Novel beta-lactamase inhibitor+monobactam||Yes||Yes||Complicated intra-abdominal infections|
|Imipenem/ cilastatin+relebactam (MK-7655)||Phase 3||Merck & Co. Inc.||Carbapenem+novel beta-lactamase inhibitor||Yes||Yes||Complicated urinary tract infections, acute pyelonephritis,complicated intra-abdominal infections, hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia|
|Carbavance (vaborbactam+ meropenem)||Phase 3||Rempex Pharmaceuticals Inc. (wholly owned subsidiary of The Medicines Co.)||Meropenem+novel boronic beta-lactamase inhibitor||Yes||Yes||Complicated urinary tract infections, complicated intra-abdominal infections, hospital-acquired bacterial pneumonia/ ventilator-associated bacterial pneumonia, febrile neutropenia,bacteremia, acute pyelonephritis (some indications specifically target infections caused by carbapenem- resistant Enterobacteriaceae)|
Antibiotics Currently in Clinical Development. Retrieved October 03, 2016, from http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development