Cephaloridine structure

Although most /3- lactam antibiotics bind covalently to some or all of the same six proteins, there are decided differences among them in terms of their relative affinities. For example, cefoxitin (see Table 1 for structures) fails to bind to protein 2 while cephacetrile binds very slowly to proteins 5 and 6. Cephaloridine binds most avidly to protein 1, the transpeptidase, and inhibits cell elongation and causes lysis at its minimum inhibitory concentration. On the other hand, cephalexin binds preferentially to protein 3 and causes inhibition of cell division and filament formation (75PNA2999, 77MI51002). 

Figure 7.34 The structures of the two cephalosporin antibiotics. Cephaloridine is nephrotoxic, cephalothin is not.

Cephalosporins are broad-spectrum antibiotics similar in structure to penicillin. For several cephalosporins, therapy is limited by the development of nephrotoxicity. Cephaloridine-induced nephrotoxicity has been examined extensively in laboratory animals and is characterized by an increase in blood urea nitrogen concentration within 24-48 hr, reductions in PAFI and TEA transport, and inhibition of glucose production following treatment. 

Ultrastructural changes of proximal tubular cells occur as early as 1 hour after cephaloridine administration to rabbits and are characterized by loss of brush border, less elongated mitochondria and disappearance of structures associated with endocytosis. Later ultrastructural changes include disorganization of lateral interdigitations of plasma cell membrane and mitochondrial swelling [28,29]. 

It has been shown that the renal bioactivation of xenobiotics such as the herbicides paraquat and diquat [10, 111, 112], and of p-lactams such as cephaloridine and cefsulodin [10, 40, 41] or the antitumor agent adriamycin [113, 114] can induce the generation of reactive oxygen species (oxidative stress) which can be involved in alterations of the structure and functions of cell membranes, cytoskeletal injury, mutagenicity, carcinogenicity, and cell necrosis [115-117]. 

The capacity to generate, and the amount of superoxide produced by a in vitro renal microsome system is dependent on the molecular structure of the specific (3-lactam. Superoxide production is a function of exposure time and (3-lactam concentration (Figure 5). The rank order of the magnitude of superoxide production by (3-lactams in vitro is as follows cephaloridine... 

Cephaloridine contains a quaternary nitrogen, exists as a zwitterion under physiological conditions and has structural similarities with carnitine. Proximal tubule cells are the internal sites of carnitine acylation [137]. Cephalosporin and carbapenem antibiotics inhibit carnitine tubular reabsorption [68, 138] and mitochondrial uptake of acylcarnitine leading to massive acylcarnitinuria [67]. Newer p-lactam such as cefepime and cefoselis, which possess a quaternary nitrogen as does carnitine, may also inhibit carnitine tubular reabsorption [88]. 

The results of these studies showed significant inhibition of pahnitoylcarnitine-mediate respiration by cephaloridine in vitro, whereas cephaloglycin, which lacks structural homology with carnitine, caused a greater inhibition of the mitochondrial transport and oxidation of bufyrate than cephaloridine. It is possible that the mitochondrial uptake of butyrate was not affected by cephaloridine maybe because the pyridinyl nitrogen hinders its attack on the monocarboxylate receptors. Cephalexin induced only mild in vitro toxicity to the mitochondrial uptake and oxidation of bufyrate and palmitate [67]. 

Tune BM.The nephrotoxicity of cephalosporin antibiotics-structure-activity relationships. Comm Toxicol 1986 1 (2) 145-170. Goldstein RS, Smith PFTarloff, JB, Contardi L, Rush GF, HookJB. Biochemical mechanisms of cephaloridine nephrotoxicity. Life Sell 988 42(19) 1809-1916. 

Semisynthetic Cephalosporins. Once the structure of cephalosporin C became known (98), attempts were made to find chemically modified analogs having superior biological properties. This was successfully achieved with the synthesis of cephalothin, cephaloridine, cephalogly-cine, and cephalexin (Figure 20). In the first two, in vitro potency was enhanced as much as 10,000 fold (99), in the latter two oral absorption... 

In order to quantify the conformational analogy between the dipeptide model and its adducts to the p-lactam antibiotics, a least-squares fitting procedure using the atomic coordinates was carried out (Boyd, 1979). Penicillin G, methicillin, ampicillin (anhydrate), cephaloridine, and some related antibiotic structures were used. The fit of the antibiotics and dipeptide models was based on minimizing the sum of the squares of three distances, Ri, R2, and R3 (31) by overlaying the three-dimensional structures in Cartesian space. The peptide carbonyl carbon of Gly-Gly is fitted to the p-lactam carbonyl carbon 7(8) because these are the atoms... 

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