3.4 β-Lactams
The β-lactam antibiotics (or β-lactams) essentially comprise of the penicillins, cephalosporins, imipenem, nocardicin A, aztreonam, clavulanic acid, moxalactam, and thienamycin. Interestingly,the β-lactam heterocyclic nucleus consists of a 4-membered cyclic ring with a N-atom. There exist a number of structural variants of β -lactam ring whereby the highly-strained β-lactam nucleus is strategically stabilized by means of the fusion of a variety of either 5-membered or 6-membered heterocyclic moieties to give rise to a wide spectrum of newer antibiotics as enumerated below.
β -Lactam Variants
A few important compounds belonging to the category of so called ‘other b-lactams’, such as: thienamycin, aztreonam, norcardicin A, imipenem and meropenem shall be treated separately as under:
3.4.1 Thienamycin
Biological Source It belongs to the first member of a family of des-thia-carbapenam nucleus antibiotics with a thioethylamine side-chain strategically positioned on the enamine portion of the fused 5-membered ring. It is obtained from cultures of Streptomyces cattleya.
Chemical Structure
[5R-[5α, 6α (R*)]]-3 [(2-Aminoethyl) thio]-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo [3, 2, 0]-hept-2-ene-2-carboxylic acid; (C11H16N2O4S).
Characteristic Features
1. It is obtained as a white hygroscopic solid powder.
2. Its specific optical rotation [α]D27 + 82.7° (C = 1.0 in water).
3. It has uvmax (water pH 4.8): 296.5 nm (ε 7900); (pH 2): 309 nm; and (pH 12): 300.5 nm.
4. It is found to be freely soluble in water; and sparingly soluble in methanol.
5. In dilute solution its stability is observed to be optimal between pH 6.7, declining with unusual rapidity above that range.
6. It is found to be susceptible to inactivation by dilute solutions of hydroxylamine and cysteine.
3.4.2 Aztreonam
Synonyms Azthreonam; Azactam; Azonam; Aztreon; Nebactam; Primbactam; SQ-26776.
Biological Sources Aztreonam enjoys the reputation of being the first totally synthetic monocyclic β-lactam (monobactam) antibiotic.
Chemical Structure
[2S-[2a, 3b(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-2-methyl-4-oxo-1-sulfo-3-azetidinyl) amino]-2-oxoethylidene] amino]oxy]-2-methylpropanoic acid; (C13H17N5O8S2).
Characteristic Features
1. It is obtained as white crystalline odourless powder which decomposes at 227°C.
2. Solubility Profile: It is found to be very slightly soluble in ethanol; slightly soluble in methanol; soluble in DMF, DMSO; and almost insoluble in toluene, chloroform, ethyl acetate.
Uses It offers a significantly high degree of resistance to β-lactamases and displays specific activity Vs aerobic Gram-negative rods.
3.4.3 Imipenem
Synonyms Imipemide; N-fomimidoylthienamycin monohydrate; MK-787.
Biological Source Imipenem is an extremely broad-spectrum semi-synthetic antibiotic produced by S. cuttleya. It is being recognized as the first stable derivative of thienamycin.
Chemical Structure
[5R-[5α, 6α (R*)]]-6-(1-Hydroxyethyl)-3[[2-[(iminomethyl) amino] ethyl] thio]-7-oxo-1-azabicyclo-[3, 2, 0] hept-2-ene-2-carboxylic acid monohydrate; (C12H17N3O4S.H2O).
Preparation It is obtained as a crystalline derivative of thienamycin by the method suggested by Leanza et al.*
Characteristic Features
1. It is obtained as crystals from a mixture of water and ethanol.
2. It has specific optical rotation [α]D25 + 86.8° (C = 0.05 in 0.1 M phosphate pH 7).
3. It has dissociation constants pKa1 ~ 3.2, pKa2 ~ 9.9.
4. It shows uvmax (water): 299 nm (ε 9670, 98% NH2OH ext.)
5. It has a solubility profile (mg . ml–1): water 10, methanol 5, ethanol 0.2, acetone < 0.1, dimethyl formamide < 0.1, and dimethyl sulphoxide 0.3.
Note: It is available in combination with cilastatin sodium as Imipem, Primaxin, Tan Acid,
Tienam, Tracix, Zienam.
Uses
1. It exhibits a broader antibacterial spectrum than any other β-lactams.
2. It happens to surpass cephalosporins against staphylococci, equals penicillin G against streptococci, equals third generation cephalosporins against most aerobic Gram-negative bacilli and is found to be fairly comparable to ceftazidine against Ps aeruginosa.
3. It is also equally comparable to both metronidazole and clindamycin against the anaerobes.
4. It is specifically recommended for the treatment, control and management of mixed bacterial infections.
3.4.4 Meropenem
Synonyms Merrem; Meronem; ICI-194660; SM-7338.
Biological Source It is also another semi-synthetic structural analogue of thienamycin, produced by S. cuttleya by the method proposed by Sunagawa et al.**
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* Leanza W.J. et al., J. Med. Chem., 22, 1435 (1979).
** M. Sunagawa et al., Eur. pat. Appl. 126, 587; M. Sunagawa, U.S. Pat. 4, 943, 569 (1984, 1990 both to Sumitomo).
Chemical Structure
[4R-[3 (3S*, 5S*) 4α, 5β, 6β (R*)]]-3-[[5-[(Dimethylamino) carbonyl]-3-pyrrolidinyl] thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo [3, 2, 0] hept-2-ene-2-carboxylic acid trihydrate; (C17H25N3O5S.3H2O).
Characteristic Features
1. It is obtained as white to pale yellow crystalline powder.
2. The colour of its solutions vary from colourless to yellow depending on the concentration.
3. Solubility Profile: It is found to be sparingly soluble in water; soluble in 5% monobasic sodium phosphate [H2NaO4P] solution; very slightly soluble in ethanol; and practically insoluble in acetone or ether.
Uses
1. The resistance of meropenem to most β-lactamases is fairly good.
2. It has a similar distribution as imipenem.
3. It is not degraded by renal dehydropeptidases.
4. It possesses slightly different affinity for specific PBPs* (primary target includes PBPs 2 and 3) depending on the strain of Gram-negative microorganisms.
3.4.5 Nocardicin A
Biological Sources It is a monocyclic β-lactam (monobactam) antibiotic with antimicrobial activity that specifically inhibits bacterial cell wall biosynthesis. In short, nocardicins A, B, C, D, E, F, G have been isolated and identified duly. All are produced by Nocardia uniformis subspecies tsuyamenesis, A being the most important component. However, nocardicin A has also been produced by Actinosynnema mirum.**
Chemical Structure
[3S-[1(S*), 3R* [Z(S*)]]]-3-[[[4-(3-Amino-3-carboxypropoxy) phenyl] (hydroxy imino) acetyl]-amino]-α-(4-hydroxyphenyl)-2-oxo-1-azetidineacetic acid; [C23H24N4O9].
Isolation Nocardicin A has been isolated and characterized by Aoki et al.*
Characteristic Features
1. It is obtained as colourless needles from acidic water having mp 214–216°C (decomposes).
2. It has specific optical rotation [α]D25-135° (for the sodium salt).
3. Its uvmax (1/15 M phosphate buffer); 272 nm (E1%1cm310); (0.1 N. NaOH): 244, 283 nm (E1% 1cm 460, 270).
4. It is found to be soluble in alkaline solutions; slightly soluble in methanol; and practically insoluble in chloroform, ethyl acetate, solvent ether.
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* Penicillin Binding Proteins.
