β-lactamases

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β-lactamases
β-lactamases
Ribbon and surface model of the β-lactamase from Citrobacter sedlaki with imipinem ligand, according to PDB  3BFC
Enzyme classification
EC, category 3.5.2.6 ,  hydrolase
Response type hydrolysis
Substrate β-lactam + H 2 O
Products β-substituted amino acid
Occurrence
Parent taxon bacteria

β-Lactamases are enzymes that are produced by numerous bacteria . They hydrolyze a common structural component of the β-lactam antibiotics , the β-lactam ring, and thereby prevent these drugs from working . Depending on the starting point, a distinction is made between penicillinases , cephalosporinases and carbapenemases . β-lactamases therefore play an important role in the feared antibiotic resistance of bacteria. The genetic information for the synthesis of β-lactamases is inherited both chromosomally and plasmid .

Catalyzed reaction

A β-lactamase catalyzes the hydrolytic opening of the lactam four-membered ring of β-lactam antibiotics :

β-lactamase cleaves the four-ring lactam, then decarboxylates the intermediate.

The ring opening product usually decarboxylates spontaneously. The irreversible binding of the ring-opening products to the body's own proteins can trigger allergic reactions. This creates a full antigen that is recognized by the body's immune system as a foreign protein and sets the corresponding defense mechanisms in motion. This results in a sensitization that can lead to allergic reactions. The allergic reactions can range from mild skin symptoms to anaphylactic shock .

classification

In the meantime, the molecular classification according to Ambler, which is also relatively simple and easy to understand, has become widely accepted:

class biochemistry Examples
A. Serine β-lactamases plasmid-coded penicillinases from staphylococci , E. coli and Klebsiella (e.g. TEM-1, SHV-1), ESBL (e.g. CTX-M-15)
B. Metallo-β-lactamases certain carbapenemases such as NDM-1
C. Serine β-lactamases Cephalosporinases (AmpC, e.g. chromosomal in Enterobacter cloacae )
D. Serine β-lactamases Oxacillinases (e.g. OXA-48 in Enterobacteriaceae, most common class of beta-lactamases in Acinetobacter baumannii , e.g. OXA-58)

There is also a more frequently used functional classification according to Bush and Jacoby, which is based on the respective substrate spectrum.

Examples

Extended spectrum β-lactamases (ESBL, class A)

Extended spectrum β-lactamases, on the other hand, can split a larger (expanded) spectrum of β-lactam-containing antibiotics. By a point mutation in the β-lactam ase expressing genes are bacteria with such altered genes capable of producing the extended-spectrum β-lactamase. The genes for the ESBL are on plasmids that can be passed on from bacterium to bacterium. Bacteria that produce ESBL are resistant to penicillins , cephalosporins and monobactams . Mainly E. coli and Klebsiella ( Gram-negative bacteria) carry ESBL genes.

In the case of severe infections, the only remedies of choice are carbapenems , tigecycline or colistin .

Carbapenemases

Carbapenemases are β-lactamases which, in addition to penicillins and cephalosporins, can also split carbapenems . A large number of variants from Gammaproteobacteria and Bacteroidetes are known of these enzymes . In 1998, 18 patients died in a New York clinic from Klebsiellae who carried carbapenemase KPC-2.

NDM-1 (class B)

NDM-1, in full: New Delhi metallo-beta-lactamase , is the name of both a special carbapenemase and the gene that expresses this enzyme in bacteria. There was a lot of media coverage when NDM-1, which is mainly found in India and Pakistan , was discovered in the enterobacteria Escherichia coli and Klebsiella pneumoniae in a British hospital . Previous cases in Great Britain , the Netherlands , Australia and Sweden resulted in part from operations (especially cosmetic surgery) in the first-mentioned Asian countries. All bacteria that have the genetic information NDM-1 can no longer be effectively combated as multi-resistant pathogens with almost all known antibiotics. Even the carbapenems, which are otherwise intended in medicine for emergencies of bacterial infections, have sometimes proven to be ineffective because they can be split by some β-lactamases. Only tigecycline and colistin are consistently effective.

NDM-2 (class B)

NDM-2, the first variant of NDM-1, was first detected in Germany (Bochum) in 2011 in a case report of a patient from an Egyptian hospital. When the pathogen ( Acinetobacter baumannii ) was sequenced with primers for NDM-1, a point mutation (position 82) was found which resulted in an amino acid exchange ( proline → alanine ) in the protein.

proof

In order to be able to easily detect β-lactamases photometrically , the nitrocefin was developed as a cephalosporin-like compound, because the nitrocefin changes its color from yellow to red when broken down by the β-lactamases. The optimal wavelength for measurement is around 486  nm .

Web links

Individual evidence

  1. ↑ Bernd Schäfer: Natural substances in the chemical industry , Spektrum Akademischer Verlag, 2007, pp. 196–197, ISBN 978-3-8274-1614-8 .
  2. ^ Karen Bush, George A. Jacoby: Updated Functional Classification of β-Lactamases . In: Antimicrobiol Agents and Chemotherapy . tape 54 , no. 3 . American Society for Microbiology , Washington 2010, pp. 969-976 , PMID 19995920 , PMC 2825993 (free full text).
  3. ↑ a b Laboratory information: What is "ESBL"? (pdf; 84 kB) General information about extended-spectrum beta-lactamase (ESBL) producing gram-negative germs and hygiene measures. Laboratory Dr. Fenner and colleagues, March 2008, accessed on May 27, 2011 : “There are only a few antibiotics available for treating these infections, e. B. Carbapenems (Imipenem or Meropenem), Tigecycline or Colistin. "
  4. ↑ Reinhard Wandtner: Deadly super bacterium. In the race with resistant pathogens. FAZ, August 16, 2010, accessed on August 17, 2010 .
  5. ↑ Kumarasamy et al .: Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study . In: The Lancet Infectious Diseases , Early Online Publication, August 11, 2010, doi: 10.1016 / S1473-3099 (10) 70143-2 .
  6. ^ D Yong, MA Toleman, CG Giske, HS Cho, K Sundman, K Lee, TR. Walsh: Characterization of a new metallo-beta-lactamase gene, bla (NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India . In: Antimicrob Agents Chemother . 53, No. 12, December 2009, pp. 5046-5054. doi : 10.1128 / AAC.00774-09 . PMID 19770275 . PMC 2786356 (free full text).
  7. ^ M Kaase, P Nordmann, TA Wichelhaus, SG Gatermann, RA Bonnin, L. Poirel: NDM-2 carbapenemase in Acinetobacter baumannii from Egypt . In: J Antimicrob Chemother . 66, No. 6, March 2011, pp. 1260-1262. PMID 21427107 .