Β-Lactam antibiotic

β-Lactam antibiotics are indicated for the prevention and treatment of bacterial infections caused by susceptible organisms. At first, β-lactam antibiotics were mainly active only against gram-positive bacteria, yet the recent development of broad-spectrum β-lactam antibiotics active against various gram-negative organisms has increased their usefulness.{{citation needed|date=March 2023}}

In uninflamed (normal) brain meninges, the penetration of beta-lactam antibiotics is low, at 0.15 of AUC_CSF/AUC_S ratio (the ratio of area under curve of cerebrosopinal fluid against area under curve of serum).{{Cite journal |vauthors=Nau R, Sörgel F, Eiffert H |date=October 2010 |title=Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections |journal=Clinical Microbiology Reviews |volume=23 |issue=4 |pages=858–83 |doi=10.1128/CMR.00007-10 |pmc=2952976 |pmid=20930076}}

==Adverse effects==

Common adverse drug reactions for the β-lactam antibiotics include diarrhea, nausea, rash, urticaria, superinfection (including candidiasis).Rossi S (ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. {{ISBN|0-9578521-4-2}}.

Infrequent adverse effects include fever, vomiting, erythema, dermatitis, angioedema, pseudomembranous colitis.

Pain and inflammation at the injection site is also common for parenterally administered β-lactam antibiotics.{{citation needed|date=March 2023}}

Immunologically mediated adverse reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent (a small fraction of which are truly IgE-mediated allergic reactions, see amoxicillin rash). Anaphylaxis will occur in approximately 0.01% of patients.{{Cite journal |last=Pichichero ME |date=April 2005 |title=A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients |journal=Pediatrics |volume=115 |issue=4 |pages=1048–57 |doi=10.1542/peds.2004-1276 |pmid=15805383 |s2cid=21246804}} There is perhaps a 5–10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems;{{Citation needed|date=January 2022}} but this figure has been challenged by various investigators.{{Who|date=January 2022}}{{Citation needed|date=January 2022}}

Nevertheless, the risk of cross-reactivity is sufficient to warrant the contraindication of all β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic. Rarely, allergic reactions have been triggered by exposure from kissing and sexual contact with a partner who is taking these antibiotics.{{Cite journal |last=Liccardi |first=Gennaro |last2=Caminati |first2=Marco |last3=Senna |first3=Gianenrico |last4=Calzetta |first4=Luigino |last5=Rogliani |first5=Paola |date=October 2017 |title=Anaphylaxis and intimate behaviour |url=https://pubmed.ncbi.nlm.nih.gov/28742538 |url-status=live |journal=Current Opinion in Allergy and Clinical Immunology |volume=17 |issue=5 |pages=350–355 |doi=10.1097/ACI.0000000000000386 |issn=1473-6322 |pmid=28742538 |s2cid=13925217 |archive-url=https://web.archive.org/web/20230425010025/https://pubmed.ncbi.nlm.nih.gov/28742538/ |archive-date=April 25, 2023 |access-date=February 27, 2021}}

A Jarisch–Herxheimer reaction may occur after initial treatment of a spirochetal infection such as syphilis with a β-lactam antibiotic.{{cn|date=September 2024}}

File:Penicillin inhibition.svg

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| footer = In the absence of β-lactam antibiotics (left), the cell wall plays an important role in bacterial reproduction. Bacteria attempting to grow and divide in the presence of β-lactam antibiotics (right) fail to do so, and instead shed their cell walls, forming osmotically fragile spheroplasts.{{Cite journal |last=Cushnie |first=T. P. |last2=O'Driscoll |first2=N. H. |last3=Lamb |first3=A. J. |year=2016 |title=Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action |url=https://zenodo.org/record/883501 |url-status=live |journal=Cellular and Molecular Life Sciences |volume=73 |issue=23 |pages=4471–4492 |doi=10.1007/s00018-016-2302-2 |pmc=11108400 |pmid=27392605 |s2cid=2065821 |archive-url=https://web.archive.org/web/20171007220157/https://zenodo.org/record/883501 |archive-date=October 7, 2017 |access-date=May 5, 2020 |hdl-access=free |hdl=10059/2129}}

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β-Lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in gram-positive organisms, being the outermost and primary component of the wall. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by DD-transpeptidases, also known as penicillin binding proteins (PBPs). PBPs vary in their affinity for penicillin and other β-lactam antibiotics. The number of PBPs varies between bacterial species.{{Cite book |last=Miyachiro |first=M. M. |title=Macromolecular Protein Complexes II: Structure and Function |last2=Contreras-Martel |first2=C. |last3=Dessen |first3=A. |year=2019 |isbn=978-3-030-28150-2 |series=Subcellular Biochemistry |volume=93 |pages=273–289 |chapter=Penicillin-Binding Proteins (PBPS) and Bacterial Cell Wall Elongation Complexes |doi=10.1007/978-3-030-28151-9_8 |pmid=31939154 |s2cid=210814189}}

β-Lactam antibiotics are analogues of {{Smallcaps|d}}-alanyl-{{Smallcaps|d}}-alanine—the terminal amino acid residues on the precursor NAM/NAG-peptide subunits of the nascent peptidoglycan layer. The structural similarity between β-lactam antibiotics and {{Smallcaps|d}}-alanyl-{{Smallcaps|d}}-alanine facilitates their binding to the active site of PBPs. The β-lactam nucleus of the molecule irreversibly binds to (acylates) the Ser₄₀₃ residue of the PBP active site. This irreversible inhibition of the PBPs prevents the final crosslinking (transpeptidation) of the nascent peptidoglycan layer, disrupting cell wall synthesis.{{Cite journal |last=Fisher |first=J. F. |last2=Meroueh |first2=S. O. |last3=Mobashery |first3=S. |year=2005 |title=Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity |journal=Chemical Reviews |volume=105 |issue=2 |pages=395–424 |doi=10.1021/cr030102i |pmid=15700950}}

β-Lactam antibiotics block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This is supporting the endosymbiotic theory and indicates an evolution of plastid division in land plants.{{Cite journal |last=Kasten |first=B. |last2=Reski |first2=R. |date=January 1, 1997 |title=β-Lactam antibiotics inhibit chloroplast division in a moss (Physcomitrella patens) but not in tomato (Lycopersicon esculentum) |journal=Journal of Plant Physiology |volume=150 |issue=1 |pages=137–140 |bibcode=1997JPPhy.150..137K |doi=10.1016/S0176-1617(97)80193-9}}

Under normal circumstances, peptidoglycan precursors signal a reorganisation of the bacterial cell wall and, as a consequence, trigger the activation of autolytic cell wall hydrolases. Inhibition of cross-linkage by β-lactams causes a build-up of peptidoglycan precursors, which triggers the digestion of existing peptidoglycan by autolytic hydrolases without the production of new peptidoglycan. As a result, the bactericidal action of β-lactam antibiotics is further enhanced.{{citation needed|date=March 2023}}

Another possibility that has been proposed to account for much of the cytotoxicity of β-lactams focuses on the oxidation of the guanine nucleotide in the bacterial nucleotide pool.{{Cite journal |last=Foti |first=James J. |last2=Devadoss |first2=Babho |last3=Winkler |first3=Jonathan A. |last4=Collins |first4=James J. |last5=Walker |first5=Graham C. |date=April 20, 2012 |title=Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics |journal=Science |volume=336 |issue=6079 |pages=315–319 |bibcode=2012Sci...336..315F |doi=10.1126/science.1219192 |pmc=3357493 |pmid=22517853}} The incorporation of oxidized guanine nucleotide into DNA could cause cytotoxicity. Bacterial cytotoxicity could arise from incomplete repair of closely spaced 8-oxo-2'-deoxyguanosine lesions in the DNA resulting in double-strand breaks.

{{See also|β-Lactam#Reactions|l1=β-Lactam reactivity}}

Two structural features of β-lactam antibiotics have been correlated with their antibiotic potency.{{Cite journal |last=Nangia |first=Ashwini |last2=Biradha |first2=Kumar |last3=Desiraju |first3=Gautam R. |date=1996 |title=Correlation of biological activity in β-lactam antibiotics with Woodward and Cohen structural parameters—a Cambridge database study |journal=Journal of the Chemical Society, Perkin Transactions 2 |issue=5 |pages=943–953 |doi=10.1039/p29960000943 |issn=1364-5471}} The first is known as "Woodward's parameter", h, and is the height (in angstroms) of the pyramid formed by the nitrogen atom of the β-lactam as the apex and the three adjacent carbon atoms as the base.{{Cite journal |last=Woodward |first=R. B. |date=May 16, 1980 |title=Penems and related substances |journal=Philosophical Transactions of the Royal Society of London B: Biological Sciences |volume=289 |issue=1036 |pages=239–250 |bibcode=1980RSPTB.289..239W |doi=10.1098/rstb.1980.0042 |issn=0962-8436 |pmid=6109320}} The second is called "Cohen's parameter", c, and is the distance between the carbon atom of the carboxylate and the oxygen atom of the β-lactam carbonyl.{{Cite journal |last=Cohen |first=N. Claude |date=February 1, 1983 |title=.beta.-Lactam antibiotics: geometrical requirements for antibacterial activities |journal=Journal of Medicinal Chemistry |volume=26 |issue=2 |pages=259–264 |doi=10.1021/jm00356a027 |issn=0022-2623 |pmid=6827544}} This distance is thought to correspond to the distance between the carboxylate-binding site and the oxyanion hole of the PBP enzyme. The best antibiotics are those with higher h values (more reactive to hydrolysis) and lower c values (better binding to PBPs).

By definition, all β-lactam antibiotics have a β-lactam ring in their structure. The effectiveness of these antibiotics relies on their ability to reach the PBP intact and their ability to bind to the PBP. Hence, there are two main modes of bacterial resistance to β-lactams: enzymatic hydrolysis of the β-lactam ring and possession of altered penicillin-binding proteins.{{cn|date=September 2024}}

If the bacterium produces the enzyme β-lactamase or the enzyme penicillinase, the enzyme will hydrolyse the β-lactam ring of the antibiotic, rendering the antibiotic ineffective.{{Cite journal |last=Drawz |first=S. M. |last2=Bonomo |first2=R. A. |year=2010 |title=Three decades of β-lactamase inhibitors |journal=Clinical Microbiology Reviews |volume=23 |issue=1 |pages=160–201 |doi=10.1128/CMR.00037-09 |pmc=2806661 |pmid=20065329}} (An example of such an enzyme is New Delhi metallo-beta-lactamase 1, discovered in 2009.) The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer (plasmid-mediated resistance), and β-lactamase gene expression may be induced by exposure to β-lactams.{{citation needed|date=March 2023}}

Image:Clavulanic acid.svg]]

Image:Amoxicillin.svg]]

The production of a β-lactamase by a bacterium does not necessarily rule out all treatment options with β-lactam antibiotics. In some instances, β-lactam antibiotics may be co-administered with a β-lactamase inhibitor. For example, Augmentin (FGP) is made of amoxicillin (a β-lactam antibiotic) and clavulanic acid (a β-lactamase inhibitor). The clavulanic acid is designed to overwhelm all β-lactamase enzymes, and effectively serve as an antagonist so that the amoxicillin is not affected by the β-lactamase enzymes. Another β-lactam/β-lactamase inhibitor combination is piperacillin/tazobactam with a broad spectrum of antibacterial activity that includes gram-positive and -negative aerobic and anaerobic bacteria. The addition of tazobactam to piperacillin has enhanced its stability against a wide range of β-lactamase enzymes including some Extended-Spectrum β-lactamases.{{Cite journal |last=Gin |first=Alfred |last2=Dilay |first2=Leanne |last3=Karlowsky |first3=James A |last4=Walkty |first4=Andrew |last5=Rubinstein |first5=Ethan |last6=Zhanel |first6=George G |date=June 2007 |title=Piperacillin–tazobactam: a β-lactam/β-lactamase inhibitor combination |url=http://www.tandfonline.com/doi/full/10.1586/14787210.5.3.365 |journal=Expert Review of Anti-infective Therapy |language=en |volume=5 |issue=3 |pages=365–383 |doi=10.1586/14787210.5.3.365 |issn=1478-7210 |pmid=17547502 |s2cid=68837323 |url-access=subscription}}

Other β-lactamase inhibitors such as boronic acids are being studied in which they irreversibly bind to the active site of β-lactamases. This is a benefit over clavulanic acid and similar β-lactam competitors, because they cannot be hydrolysed, and therefore rendered useless. Extensive research is currently being done to develop tailored boronic acids to target different isozymes of beta-lactamases.{{Cite journal |last=Leonard |first=David A. |last2=Bonomo |first2=Robert A. |last3=Powers |first3=Rachel A. |date=November 19, 2013 |title=Class D β-Lactamases: a reappraisal after five decades |journal=Accounts of Chemical Research |volume=46 |issue=11 |pages=2407–2415 |doi=10.1021/ar300327a |issn=0001-4842 |pmc=4018812 |pmid=23902256}}

However, in all cases where infection with β-lactamase-producing bacteria is suspected, the choice of a suitable β-lactam antibiotic should be carefully considered prior to treatment. In particular, choosing appropriate β-lactam antibiotic therapy is of utmost importance against organisms which harbor some level of β-lactamase expression. In this case, failure to use the most appropriate β-lactam antibiotic therapy at the onset of treatment could result in selection for bacteria with higher levels of β-lactamase expression, thereby making further efforts with other β-lactam antibiotics more difficult.{{Cite journal |last=Macdougall C |date=2011 |title=Beyond susceptible and resistant Part I: treatment of infections due to Gram-negative organisms with inducible B-lactamases |journal=Journal of Pediatric Pharmacology and Therapeutics |volume=16 |issue=1 |pages=23–30 |doi=10.5863/1551-6776-16.1.23 |pmc=3136230 |pmid=22477821}}

In the context of medical pharmacology, penicillins, cephalosporins, and carbapenems, while all have the β-lactam ring that serves as the fundamental structure, also have an auxiliary ring that carries a carboxylate group that is positioned on the same side as the carbonyl group within the β-lactam ring, and, as such, this structural configuration is critical to their antimicrobial activity.{{Cite journal |vauthors=Kim D, Kim S, Kwon Y, Kim Y, Park H, Kwak K, Lee H, Lee JH, Jang KM, Kim D, Lee SH, Kang LW |date=March 2023 |title=Structural Insights for β-Lactam Antibiotics |journal=Biomol Ther (Seoul) |volume=31 |issue=2 |pages=141–147 |doi=10.4062/biomolther.2023.008 |pmc=9970833 |pmid=36788654}} Bacterial resistance to these antibiotics primarily occurs through the production of β-lactamases, enzymes that hydrolyze the amide bond of the β-lactam ring, thereby eliminating the antimicrobial activity of these antibiotics. This resistance mechanism underscores the importance of the structural integrity of the β-lactam ring for the antibiotic's function.{{Cite journal |vauthors=Ahmadvand P, Avillan JJ, Lewis JA, Call DR, Kang C |date=May 2022 |title=Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin |journal=Int J Mol Sci |volume=23 |issue=9 |page=5229 |doi=10.3390/ijms23095229 |pmc=9100253 |pmid=35563620 |doi-access=free}} The color change from colorless or light yellow to amber or even red in an aqueous solution of a β-lactam antibiotic can denote β-lactamase hydrolysis of amide bonds in the β-lactam ring.{{Cite web |title=Archived copy |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/050585s068lbl.pdf |url-status=live |archive-url=https://web.archive.org/web/20220216203718/https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/050585s068lbl.pdf |archive-date=February 16, 2022 |access-date=February 22, 2024}}{{Cite book |title=Principles and Practice of Pediatric Infectious Disease |vauthors=Christenson JC, Korgenski EK |date=2008 |publisher=W.B. Saunders |isbn=978-0-7020-3468-8 |pages=1341–1352 |chapter=Laboratory Diagnosis of Infection Due to Bacteria, Fungi, Parasites, and Rickettsiae |doi=10.1016/B978-0-7020-3468-8.50292-3 |chapter-url=https://doi.org/10.1016/B978-0-7020-3468-8.50292-3}} This is often observed with a chromogenic β-lactamase substrate like ceftriaxone, merapenem, or nitrocefin,{{Cite web |title=Archived copy |url=https://www.sigmaaldrich.com/MD/en/product/mm/484400 |url-status=live |archive-url=https://web.archive.org/web/20240222173130/https://www.sigmaaldrich.com/MD/en/product/mm/484400 |archive-date=February 22, 2024 |access-date=February 22, 2024}} that undergoes a distinctive color change from yellow to red as the amide bond in the β-lactam ring is hydrolyzed by β-lactamase. This color change is a visual indicator of the presence and activity of β-lactamase enzymes, which are responsible for conferring resistance to β-lactam antibiotics in many bacterial species. The hydrolysis of the β-lactam ring by β-lactamase enzymes renders the antibiotic ineffective, thereby allowing the bacteria to survive in the presence of the antibiotic.{{Cite journal |vauthors=Palzkill T |date=January 2013 |title=Metallo-β-lactamase structure and function |journal=Ann N Y Acad Sci |volume=1277 |issue=1 |pages=91–104 |bibcode=2013NYASA1277...91P |doi=10.1111/j.1749-6632.2012.06796.x |pmc=3970115 |pmid=23163348}} Some β-lactam antibiotics like ceftriaxone and meropenem are known to be relatively unstable in solution, especially when stored for extended periods, and degrade in an aqueous solution even without the presence of β-lactamase.{{Cite journal |vauthors=Fawaz S, Barton S, Whitney L, Swinden J, Nabhani-Gebara S |date=2019 |title=Stability of Meropenem After Reconstitution for Administration by Prolonged Infusion |url=https://doi.org/10.1177/0018578718779009 |url-status=live |journal=Hospital Pharmacy |volume=54 |issue=3 |pages=190–196 |doi=10.1177/0018578718779009 |pmc=6535930 |pmid=31205331 |archive-url=https://web.archive.org/web/20240227031516/https://journals.sagepub.com/doi/10.1177/0018578718779009 |archive-date=February 27, 2024 |access-date=February 22, 2024}} For ceftriaxone, the color of solutions can range from light yellow to amber, depending on the length of storage, concentration, and diluent used.{{Cite web |title=Ceftriaxone: Package Insert |url=https://www.drugs.com/pro/ceftriaxone.html |archive-url=https://web.archive.org/web/20230402222612/https://www.drugs.com/pro/ceftriaxone.html |archive-date=April 2, 2023}}{{Cite web |archive-url=https://web.archive.org/web/20240222172948/https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/0550585s063lbl.pdf |title=ROCEPHIN for Injection Package Insert |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/0550585s063lbl.pdf |archive-date=22 February 2024 |url-status=live |publisher=Roche Pharmaceuticals |website=accessdata.fda.gov}} A study found that meropenem concentrations dropped to 90% of the initial concentration at 7.4 hours at 22°C and 5.7 hours at 33°C, indicating degradation over time.

As a response to the use of β-lactams to control bacterial infections, some bacteria have evolved penicillin binding proteins with novel structures. β-Lactam antibiotics cannot bind as effectively to these altered PBPs, and, as a result, the β-lactams are less effective at disrupting cell wall synthesis. Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA){{Cite journal |last=Ubukata |first=K. |last2=Nonoguchi |first2=R. |last3=Matsuhashi |first3=M. |last4=Konno |first4=M. |year=1989 |title=Expression and inducibility in Staphylococcus aureus of the mecA gene, which encodes a methicillin-resistant S. aureus-specific penicillin-binding protein |journal=Journal of Bacteriology |volume=171 |issue=5 |pages=2882–5 |doi=10.1128/jb.171.5.2882-2885.1989 |pmc=209980 |pmid=2708325}} and penicillin-resistant Streptococcus pneumoniae. Altered PBPs do not necessarily rule out all treatment options with β-lactam antibiotics.{{medical citation needed|date=February 2024}}

{{also|List of β-lactam antibiotics}}

{{Beta-lactam core structures}}

β-Lactams are classified according to their core ring structures.{{Cite journal |last=Dalhoff |first=A. |last2=Janjic |first2=N. |last3=Echols |first3=R. |year=2006 |title=Redefining penems |journal=Biochemical Pharmacology |volume=71 |issue=7 |pages=1085–1095 |doi=10.1016/j.bcp.2005.12.003 |pmid=16413506}}

• β-Lactams fused to saturated five-membered rings:
• β-Lactams containing thiazolidine rings are named penams.
• β-Lactams containing pyrrolidine rings are named carbapenams.
• β-Lactams fused to oxazolidine rings are named oxapenams or clavams.
• β-Lactams fused to unsaturated five-membered rings:
• β-Lactams containing 2,3-dihydrothiazole rings are named penems.
• β-Lactams containing 2,3-dihydro-1H-pyrrole rings are named carbapenems.
• β-Lactams fused to unsaturated six-membered rings:
• β-Lactams containing 3,6-dihydro-2H-1,3-thiazine rings are named cephems.
• β-Lactams containing 1,2,3,4-tetrahydropyridine rings are named carbacephems.
• β-Lactams containing 3,6-dihydro-2H-1,3-oxazine rings are named oxacephems.
• β-Lactams not fused to any other ring are named monobactams.

By convention, the bicyclic β-lactams are numbered starting with the position occupied by sulfur in the penams and cephems, regardless of which atom it is in a given class. That is, position 1 is always adjacent to the β-carbon of β-lactam ring. The numbering continues clockwise from position one until the β-carbon of β-lactam is reached, at which point numbering continues counterclockwise around the lactam ring to number the remaining to carbons. For example, the nitrogen atom of all bicyclic β-lactams fused to five-membered rings is labelled position 4, as it is in penams, while in cephems, the nitrogen is position 5.{{citation needed|date=February 2024}}

The numbering of monobactams follows that of the IUPAC; the nitrogen atom is position 1, the carbonyl carbon is 2, the α-carbon is 3, and the β-carbon 4.{{citation needed|date=February 2024}}

To date, two distinct methods of biosynthesizing the β-lactam core of this family of antibiotics have been discovered. The first pathway discovered was that of the penams and cephems. This path begins with a nonribosomal peptide synthetase (NRPS), ACV synthetase (ACVS), which generates the linear tripeptide δ-(L-α-aminoadipyl)-L-cysteine-D-valine (ACV). ACV is oxidatively cyclized (two cyclizations by a single enzyme) to bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS) to form the penam core structure.{{Cite journal |last=Lundberg |first=M. |last2=Siegbahn |first2=P. E. M. |last3=Morokuma |first3=K. |year=2008 |title=The mechanism for isopenicillin N synthase from density-functional modeling highlights the similarities with other enzymes in the 2-His-1-carboxylate family |url=http://uu.diva-portal.org/smash/get/diva2:396502/FULLTEXT01 |url-status=live |journal=Biochemistry |volume=47 |issue=3 |pages=1031–1042 |doi=10.1021/bi701577q |pmid=18163649 |archive-url=https://web.archive.org/web/20170922053330/http://uu.diva-portal.org/smash/get/diva2:396502/FULLTEXT01 |archive-date=September 22, 2017 |access-date=October 28, 2017}} Various transamidations lead to the different natural penicillins.

File:Beta-lactam closure routes.png

The biosynthesis of cephems branch off at isopenicillin N by an oxidative ring expansion to the cephem core. As with the penams, the variety of cephalosporins and cephamycins come from different transamidations, as is the case for the penicillins.{{cn|date=September 2024}}

While the ring closure in penams and cephems is between positions 1 and 4 of the β-lactam and is oxidative, the clavams and carbapenems have their rings closed between positions 1 and 2 of the ring. β-lactam synthetases are responsible for these cyclizations, and the carboxylate of the open-ring substrates is activated by ATP.{{Cite journal |last=Bachmann |first=B. O. |last2=Li |first2=R. |last3=Townsend |first3=C. A. |year=1998 |title=β-lactam synthetase: a new biosynthetic enzyme |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=95 |issue=16 |pages=9082–9086 |bibcode=1998PNAS...95.9082B |doi=10.1073/pnas.95.16.9082 |pmc=21295 |pmid=9689037 |doi-access=free}} In clavams, the β-lactam is formed prior to the second ring; in carbapenems, the β-lactam ring is closed second in sequence.{{citation needed|date=March 2023}}

The biosynthesis of the β-lactam ring of tabtoxin mirrors that of the clavams and carbapenems. The closure of the lactam ring in the other monobactams, such as sulfazecin and the nocardicins, may involve a third mechanism involving inversion of configuration at the β-carbon.{{Cite journal |last=Townsend |first=CA |last2=Brown |first2=AM |last3=Nguyen |first3=LT |year=1983 |title=Nocardicin A: stereochemical and biomimetic studies of monocyclic β-lactam formation |journal=Journal of the American Chemical Society |volume=105 |issue=4 |pages=919–927 |doi=10.1021/ja00342a047}}

• List of β-lactam antibiotics
• ATC code J01C Beta-lactam antibacterials, penicillins
• ATC code J01D Other beta-lactam antibacterials
• Bacteria
• Cell wall
• Discovery and development of cephalosporins
• History of penicillin
• Nitrocefin

{{Reflist}}

{{Beta-lactam antibiotics}}

{{Authority control}}

{{DEFAULTSORT:Beta-lactam Antibiotic}}

Category:Nephrotoxins