Sulphonamide resistance

Although it was proposed that inhibition of HCMV DNA maturation by the benzimidazole ribonucleoside BDCRB is mediated through the UL89 gene product, and resistance to TCRB maps to the two ORFs UL89 and UL56, there was no cross-resistance of an HCMV AD 169 sulphonamide-resistant strain to BDCRB (Reefschlaeger et al. 1999). 

Bacterial resistance to antibiotics has been recognized since the first drugs were introduced for clinical use. The sulphonamides were introduced in 1935 and approximately 10 years later 20% of clinical isolates of Neisseria gonorrhoeae had become resistant. Similar increases in sulphonamide resistance were found in streptococci, coliforms and other bacteria. Penicillin was first used in 1941, when less than 1 % of Staphylococcus aureus strains were resistant to its action. By 1947,3 8% of hospital strains had acquired resistance and currently over 90% of Staph, aureus isolates are resistant to penicillin. Increasing resistance to antibiotics is a consequence of selective pressure, but the actual incidence of resistance varies between different bacterial species. For example, ampicillin resistance inEscherichia coli, presumably under similar selective pressure as Staph, aureus with penicillin, has remained at a level of 30-40% for mai years with a slow rate of increase. Streptococcus pyogenes, another major pathogen, has remained susceptible to penicillin since its introduction, with no reports of resistance in the scientific literature. Equally, it is well recognized that certain bacteria are unaffected by specific antibiotics. In other words, these bacteria have always been antibiotic-resistant. 

Huovinen P., Sundstrom L., Swedberg G. Skold O. (1995) Trimethoprim and sulphonamide resistance. 

Alteration of a metabolic pathway, for example some sulphonamide-resistant bacteria switch to using pre-formed fohc acid, rather than synthesise the precursor para-aminobenzoic acid (PABA), which is the reaction inhibited by sulphonamides. 

At least some sulphonamide-resistant bacteria can, like mammalian cells, utilize preformed folic acid for nucleic acid synthesis. 

Sulphonatnides. Sulphonamides are very resistant to the normal reagents for hydrolysis. Heating with 80 per cent, sulphuric acid at 160-170° results in rapid hydrolysis ... 

Bacteria which are almost always sensitive to the sulphonamides include Strep, pneumoniae, /3-haemolytic streptococci, Escherichia coli and Proteus mirabilis those almost always resistant include Enterococcus faecalis, Ps. aeruginosa, indole-positive Proteus and Klebsiella whereas bacteria showing a marked variation in response include Staph, aureus, gonococci, El. influenzae and hospital strains of E. coli and Pr. mirabilis. 

Chromosomal and plasmid-mediated resistance to the sulphonamides has been described... 

Two mechanisms of chromosomal resistance have been identified. A mutation of dihydropteroate synthetase (DHPS) in Strep, pneumoniae produces an altered enzyme with reduced affinity for sulphonamides. Hyperproduction of p-aminobenzoic acid (PABA) overcomes the block imposed by inhibition ofDHPS. The specific cause of PABA hyperproduction is unknown, though chromosomal mutation is the probable cause. 

Duplication ofDHPS, with the second version of the enzyme being resistant to the sulphonamides, is the cause of plasmid-acquired resistance. Two different enzymes have been identified, both with lowered affinity for the antibiotic. 

Plasmid- and transposon-mediated resistance is akin to that described for the sulphonamides, where the sensitive step is bypassed by duplication of the target with a resistant version. Many different resistant enzymes have been identified thus far. 

Plasmid-mediated resistance to sulphonamides results from the duplication of dihydropteroate synthetase (DHPS). The normal DHPS remains sensitive but the plasmid-encoded DHPS, two types (I and II) of which have been found in Gram-negative bacteria, binds considerably less of these drugs [203]. 

Resistance to penicillins and cephalosporins Resistance to polymyxins Resistance to tetracyclines Resistance to sulphonamides Mutation... 

From a clinical point of view, the sulphonamides were extremely useful for the treatment of uncomplicated urinary tract infections caused by E. coli in domiciliary practice, although their value has diminished in recent years due to resistance develop-... 

There are few absolute clinical indications for the use of sulphonamides. They have been used extensively in the past for urinary tract infections, though less now. They are used for certain respiratory infections, including that by Pneumocystis carnii, some sexually transmitted diseases (chlamidia. chancroid, trachoma), in drug-resistant malaria (with pyrimethamine), in inflammatory towel disease (sulfasalazine) and as silver sulfadiazine for topical application in infected burns. 

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