1. Medical uses

2. Mechanism of action

3. Commonly used agents

4. Beta-lactamase producing bacteria

5. Research

6. References

7. External links

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin-like antibiotics to work. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors.^[1] Although β-lactamase inhibitors have little antibiotic activity of their own,^[2] they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

Medical uses

The most important use of beta-lactamase inhibitors is in the treatment of infections known or believed to be caused by gram-negative bacteria, as beta-lactamase production is an important contributor to beta-lactam resistance in these pathogens. In contrast, most beta-lactam resistance in gram-positive bacteria is due to variations in penicillin-binding proteins that lead to reduced binding to the beta-lactam.^[3][4] The gram-positive pathogen Staphylococcus aureus produces beta-lactamases, but beta-lactamase inhibitors play a lesser role in treatment of these infections because the most resistant strains (methicillin-resistant Staphylococcus aureus) also use variant penicillin-binding proteins.^[5][6]

Mechanism of action

The Ambler classification system groups known beta-lactamase enzymes into four groups according to sequence homology and presumed phylogenetic relationships. Classes A, C and D cleave beta-lactams by a multi-step mechanism analogous to the mechanism of serine proteases. Upon binding, a serine hydroxyl group in the beta-lactamase active site forms a transient covalent bond to the beta-lactam ring carbonyl group, cleaving the beta-lactam ring in the process. In a second step, nucleophilic attack by a water molecule cleaves the covalent bond between the enzyme and the carbonyl group of the erstwhile beta-lactam. This allows the degraded beta-lactam to diffuse away and frees up the enzyme to process additional beta-lactam molecules.

Currently available beta-lactamase inhibitors are effective against Ambler Class A beta-lactamases (tazobactam, clavulanate, and sulbactam) or against Ambler Class A, C and some Class D beta-lactamases (avibactam). Like beta-lactam antibiotics, they are processed by beta-lactamases to form an initial covalent intermediate. Unlike the case of beta-lactam antibiotics, the inhibitors act as suicide substrates (tazobactam and sulbactam) which ultimately leads to the degradation of the beta-lactamase^[7]. Avibactam on the other hand does not contain a beta-lactam ring (non beta-lactam beta-lactamase inhibitor), and instead binds reversibly.^[8][9]

Ambler Class B beta-lactams cleave beta-lactams by a mechanism similar to that of metalloproteases. As no covalent intermediate is formed, the mechanism of action of marketed beta-lactamase inhibitors is not applicable. Thus the spread of bacterial strains expressing metallo beta-lactamases such as the New Delhi metallo-beta-lactamase 1 has engendered considerable concern.^[10]

Commonly used agents

Currently marketed β-lactamase inhibitors are not sold as individual drugs. Instead they are co-formulated with a β-lactam antibiotic with a similar serum half-life. This is done not only for dosing convenience, but also to minimize resistance development that might occur as a result of varying exposure to one or the other drug. The main classes of β-lactam antibiotics used to treat gram-negative bacterial infections include (in approximate order of intrinsic resistance to cleavage by β-lactamases) penicillins (especially aminopenicillins and ureidopenicillins), 3rd generation cephalosporins, and carbapenems. Individual β-lactamase variants may target one or many of these drug classes, and only a subset will be inhibited by a given β-lactamase inhibitor.^[9] β-lactamase inhibitors expand the useful spectrum of these β-lactam antibiotics by inhibiting the β-lactamase enzymes produced by bacteria to deactivate them.^[11]

• β-lactamase inhibitors with β-lactam core:
  • Tebipenem is the first carbapenem to be administered orally in the form of Tebipenem-Pivoxil. Structural and kinetic studies of tebipenem is available with M.tuberculosis beta-lactamase (BlaC).^[12]
  • Boron based transition state inhibitors or BATSIs are very potent group of beta-lactamase inhibitors. A screen of a series of BATSIs against M. tuberculosis produces very interesting result. All the BATSIs with high inhibitory effects contain a benzoic carboxylic acid group. This is indeed a great break through in studying drug resistant beta-lactamases.^[13]
  • Clavulanic acid or clavulanate, usually combined with amoxicillin (Augmentin) or ticarcillin (Timentin)
  • Sulbactam, usually combined with ampicillin (Unasyn) or Cefoperazone (Sulperazon)
  • Tazobactam, usually combined with piperacillin (Zosyn) (Tazocin)
• Non-β-lactam β-lactamase inhibitors:
  • Avibactam, approved in combination with ceftazidime (Avycaz), currently undergoing clinical trials for combination with ceftaroline
  • Relebactam (previously known as MK-7655) is undergoing Phase III clinical trials as a treatment for pneumonia and bacterial infections (as of March 1, 2016).^[14]

Beta-lactamase producing bacteria

Bacteria that can produce beta-lactamases include, but are not limited to:

• Staphylococcus
  • MRSA(Methicillin-resistant Staphylococcus aureus)
• Enterobacteriaceae:
  • Klebsiella pneumoniae
  • Citrobacter
  • Proteus vulgaris
  • Morganella
  • Salmonella
  • Shigella
  • Escherichia coli
• Haemophilus influenzae
• Neisseria gonorrhoeae
• Pseudomonas aeruginosa
• Mycobacterium tuberculosis

Research

Some bacteria can produce extended spectrum β-lactamases (ESBLs) making the infection more difficult to treat and conferring additional resistance to penicillins, cephalosporins, and monobactams.^[15]

References

External links

• {{cite journal | vauthors = Xu H, Hazra S, Blanchard JS | title = NXL104 irreversibly inhibits the β-lactamase from Mycobacterium tuberculosis | journal = Biochemistry | volume = 51 | issue = 22 | pages = 4551–7 | date = June 2012 | pmid = 22587688 | pmc = 3448018 | doi = 10.1021/bi300508r }}
• {{cite journal | vauthors = Kurz SG, Wolff KA, Hazra S, Bethel CR, Hujer AM, Smith KM, Xu Y, Tremblay LW, Blanchard JS, Nguyen L, Bonomo RA | title = Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis β-Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of β-lactam-β-lactamase inhibitor combinations | journal = Antimicrobial Agents and Chemotherapy | volume = 57 | issue = 12 | pages = 6085–96 | date = December 2013 | pmid = 24060876 | pmc = 3837893 | doi = 10.1128/AAC.01253-13 }}

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