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Resistenzmechanismen gegen Betalaktamantibiotika

Mechanisms of resistance against beta-lactam antibiotics

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Zusammenfassung

Die Strukturgemeinsamkeit der Betalaktamantibiotika ist der Betalaktamring, der auch für die inhibitorische Wirkung dieser Antibiotika auf die Zellwandsynthese verantwortlich ist. Die Zielmoleküle sind Peptidoglycan-quervernetzende Enzyme (Transpeptidasen und Carboxypeptidasen), die Betalaktamantibiotika binden können (Penicillin-Bindungs-Proteine, PBP). Die Abtötung der Bakterienzelle wird durch Betalaktamantibiotika-induzierte Freisetzung von autolytischen Enzymen initiiert. Im Gegensatz zu grampositiven Bakterien (Fehlen einer äußeren Membran) muß das Antibiotikum vor Erreichen der PBPs die Porine der äußeren Zellmembran von gramnegativen Bakterien passieren. Für die bakterielle Resistenz gegen Betalaktamantibiotika kommen deshalb in Betracht (i) die Modifikation von Porinen (Permeabilitätsbarriere) und (ii) von Penicillinbindungsproteinen (niedrige Affinität von PBP's), (iii) die Produktion von inaktivierenden Enzymen (Betalaktamasen) und (iv) die Inhibition der Freisetzung von autolytischen Enzymen. Darüber hinaus stehen den Bakterien raffinierte genetische Mechanismen zur Verfügung, um sich an die Konfrontation mit neuen Antibiotika schnell zu adaptieren. Damit auch in Zukunft die Antibiotikabehandlung von bakteriellen Infektionserkrankungen erfolgreich ist, sind Kenntnisse über Antibiotika-Resistenzmechanismen erforderlich.

Summary

Beta-lactam antibiotics share the structural feature of a beta-lactam ring. This feature is responsible for inhibition of bacterial cell wall synthesis. The target molecules are peptidoglycan cross-linking enzymes (e.g. transpeptidases and carboxypeptidases) which can bind beta-lactam antibiotics (penicillin binding proteins, PBP). Bacterial cell death is initiated by beta-lactam antibiotic-triggered release of autolytic enzymes. In contrast to gram-positive bacteria (absence of an outer membrane) the antibiotic has to penetrate through porins of the outer membrane of gram-negative bacteria before touching PBP's. Bacterial resistance to beta-lactam antibiotics includes modification of porins (permeability barrier) and of targets (low affinity of PBP's for the drug), production of inactivating enzymes (beta-lactamases) and inhibition of release of autolytic enzymes. Moreover, bacteria have developed sophisticated genetic mechanisms to adapt to treatments with novel beta-lactam antibiotics. To allow successful antibiotic treatment of bacterial infection in the future, knowledge about antibiotic resistance mechanisms is required.

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Heesemann, J. Resistenzmechanismen gegen Betalaktamantibiotika. Infection 21 (Suppl 1), S4–S9 (1993). https://doi.org/10.1007/BF01710336

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