Carbapenem
Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to beta-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomyces cattleya.[1]
Carbapenems are one of the antibiotics of last resort for many bacterial infections, such as E.coli and Klebsiella[citation needed]. Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics among these coliforms, due to production of an enzyme named NDM-1. There are currently no new antibiotics in the pipeline to combat bacteria resistant to carbapenems, and worldwide spread of the resistance gene is considered a nightmare scenario.[2]
Examples
The following drugs belong to the carbapenem class:
- Imipenem (often given as part of Imipenem/cilastatin)
- Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme to a nephrotoxic metabolite, and so is given with a dehydropeptidase inhibitor, cilastatin
- Meropenem
- Ertapenem
- Doripenem
- Panipenem/betamipron
- Biapenem
- Razupenem (PZ-601)
- PZ-601 is a carbapenem antibiotic currently being tested as having a broad spectrum of activity including strains resistant to other carbapenems.
Faropenem is closely related, but it is a penem, not a carbapenem.[3]
Uses
These agents have the broadest antibacterial spectrum compared to other beta-lactam classes such as penicillins and cephalosporins. Additionally they are generally resistant to the typical bacterial beta-lactamase enzymes, which are one of the principal beta-lactam resistance mechanisms of bacteria. However, strains of carbapenem-resistant enteric bacteria have been isolated in the United States and the United Kingdom from patients who have received recent medical care in Pakistan, Bangladesh and India.[4] These strains carry a gene called New Delhi metallo-beta-lactamase (shortened NDM-1) that is responsible for the production of a metallo-beta-lactamase enzyme that hydrolyses carbapenem [5].
Carbapenems are active against both Gram-positive, Gram-negative bacteria, and anaerobes, with the exception of intracellular bacteria (atypicals), such as the Chlamydiae. Carbapenems also are thus-far the only beta-lactams capable of inhibiting L,D-Transpeptidases [6].
Structure
The carbapenems are structurally very similar to the penicillins, but the sulfur atom in position 1 of the structure has been replaced with a carbon atom, and hence the name of the group, the carbapenems.
Biosynthesis
The carbapenams are thought to share their early biosynthetic steps in which the core ring system is formed. Malonyl-CoA is condensed with glutamate semialdehyde with concurrent formation of the five-membered ring. Next, a β-lactam synthetase uses ATP to form the β-lactam and the saturated carbapenam core. Further oxidation and ring inversion provides the basic carbapenem.
Administration
Due to their expanded spectra, the desire to avoid generation of resistance and the fact that they have generally poor oral bioavailability, they are administered intravenously in hospital settings for more serious infections. However, research is underway to develop an effective oral carbapenem.[7]
References
- ^ Birnbaum J, Kahan FM, Kropp H, MacDonald JS (1985). "Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin". Am. J. Med. 78 (6A): 3–21. doi:10.1016/0002-9343(85)90097-X. PMID 3859213.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ http://www.telegraph.co.uk/health/7939687/Can-we-stop-the-Indian-superbug.html
- ^ "Medscape.com".
- ^ "BBC News - New 'superbug' found in UK hospitals". Retrieved 10 Aug 2010.
- ^ Center for Disease Control and Prevention (2010). "Detection of Enterobacteriaceae Isolates Carrying Metallo-Beta-Lactamase --- United States, 2010". Morbidity and Mortality Weekly Report. 59 (24): 750. PMID 20577157.
{{cite journal}}: Unknown parameter|available online=ignored (help) - ^ Mainardi, Jean-Luc et al.: "Evolution of Peptidoglycan Biosynthesis under the Selective Pressure of Antibiotics in Gram-Positive Bacteria" Federation of European Microbiological Societies, 2008.
- ^ Kumagai T, Tamai S, Abe T, Hikda M (2002). "Current Status of Oral Carbapenem Development". Current Medicinal Chemistry -Anti-Infective Agents. 1: 1–14. doi:10.2174/1568012023355018.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
External links
- Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD; beginning at pp131