Sulfonamides resistance mechanisms

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

R-plasmid-mediated resistance is almost invariably associated with crossresistance to a number of related and unrelated antibiotics. The reasons for the association lie in the resistance mechanism to related compounds that have been coded, the usual presence of more than one R determinant in the same plasmid, and the frequent coexistence of several different plasmids in the same bacterial cell. As a result, use of any antibiotic can lead to development of resistance to itself and to other related and unrelated antibiotics. If, for example, a plasmid is encoded for resistance to ampicillin, tetracycline, sulfonamide, and streptomycin, exposure to any of these antibiotics results in resistance to all the others, whereas the use of a -lactamase-containing strain results in resistance to other members of this group. 

Resistance to sulfonamides is widespread in bacteria isolated from animals, and may involve chromosomal mutations or plasmid-mediated mechanisms. Chromosomal mutations cause impaired drug penetration, production of altered forms of dihydropteroate synthetase for which sulfonamides have a lowered affinity, or production of excessive PABA that overcomes the metabolic block imposed by the inhibition of dihydropteroate synthetase. A more common cause of bacterial resistance to sulfonamides is plasmid-mediated mechanisms, which may result in impaired drug penetration or the synthesis of sulfonamide-resistant dihydropteroate synthetase. There is cross-resistance among sulfonamides. 

Development of Resistance. One of the principal disadvantages of sulfonamide therapy is the emergence of dmg-resistant strains of bacteria. Resistance develops by several mechanisms overproduction of PABA (38) altered permeabiUty of the organisms to sulfonamides (39) and reduced affinity of dihydropteroate synthetase for sulfonamides while the affinity for PABA is retained (40). Sulfonamides also show cross-resistance to other sulfonamides but not to other antibacterials. In plasmodia, resistance may occur by means of a bypass mechanism in which the organisms can use preformed foHc acid (41). 

Resistance to the sulfonamides can be the result of decreased bacterial permeability to the drug, increased production of PABA, or production of an altered dihydropteroate synthetase that exhibits low affinity for sulfonamides. The latter mechanism of resistance is plasmid mediated. Active efflux of the sulfonamides has also been reported to play a role in resistance. The inhibitory effect of the sulfonamides also can be reversed by the presence of pus, tissue fluids, and drugs that contain releasable PABA. 

B. Humans cannot synthesize folic acid (A) diet is their main source. Sulfonamides selectively inhibit microbially synthesized folic acid. Incorporation (B) of PABA into microbial folic acid is competitively inhibited by sulfonamides. The TMP-SMX combination is synergistic because it acts at different steps in microbial folic acid synthesis. All sulfonamides are bacteriostatic. Inhibition of the transpeptidation reaction (C) involved in the synthesis of the bacterial cell wall is the basic mechanism of action of (3-lac-tam antibiotics Changes in DNA gyrases (D) and active efflux transport system are mechanisms for resistance to quinolones. Structural changes (E) in dihydropteroate synthetase and overproduction of PABA are mechanisms of resistance to the sulfonamides. 

Mechanism of Action A sulfonamide derivative that acts as a thiazide diuretic and antihypertensive. As a diuretic, blocks reabsorption of water and the electrolytes sodium and potassium at cortical diluting segment of distal tubule. As an antihypertensive, reduces plasma and extracellular fluid volume, decreases peripheral vascular resistance (PVR) by direct effect on blood vessels. Therapeutic Effect Promotes diuresis, reduces BP. 

Acquired resistance to sulfonamides is widespread. Mechanisms of resistance include overproduction of... 

One of the most straightforward mechanisms of antibiotic resistance is mutation of the target to a form that has less affinity for the antibiotic. Spontaneous mutations that provide some benefit to the organism occur roughly 2 x 10 per replication (reviewed in Reference 73). Exposure to certain classes of antibiotics such as the rifamycins and fluoroquinolones can induce mutation, increasing the opportunity of developing resistance (74). Point mutations are associated with resistance to virtually all antibiotics, but this form of resistance is particularly important in the clinic for the fluoroquinolones, rifamycins such as rifampin, trimethroprim, and the sulfonamides. 

Ionomer membranes based on perfluorocarbon polymers became available In the late 196O s. These materials have excellent chemical resistance, thermal stability, mechanical strength and strong acid strength, A number of functionalities have been studied. Including carboxylate, sulfonate and sulfonamide, but only the first two are available as commercial materials. Ferfluorlnated lonomers have been evaluated as membranes In a variety of applications, such as water electrolysis, fuel cells, air driers, Donnan dialysis In waste metal recovery, and acid catalysts, but the primary interest in these materials is for the permselective membrane In electrochemical processes such as In the production of chlorine and caustic (58). 

Answer A- Microbial resistance to fluoroquinolones is increasing, and some strains of Streptococcus pneumoniae are now resistant to ciprofloxacin. The mechanism can involve changes in the structure of topoisomerase IV, one of the targets of fluoroquinolones, which inhibit nucleic acid synthesis. Pneumococcal resistance to penicillins is also increasing via changes in penicillin-binding proteins (PBPs). The other mechanisms listed underlie microbial resistance to other antibiotics as follows sulfonamides (choice B), macrolides (choice C), extended-spectrum penicillins (choice D), and beta-lactams (choice E). 

A good measure of past and continuing interest in ionomer membranes issued from the development of perfluorinated ionomers, the first-announced being Nafion(44). These materials are characterized by remarkable chemical resistance, thermal stability and mechanical strength, and they have a very strong acid strength, even in the carboxylic acid form. The functionalities that have been considered include carboxylate, sulfonate, and sulfonamide, the latter resulting from the reactions of amines with the sulfonyl fluoride precursor. 

Even though the synergism observed with antifolate-sulfonamide combinations appears real, whether or not the mechanism is truly a sequential blockade is questionable. For example, it was shown that a potent DHFR inhibitor, 2,4-diaminopteroyl aspartate, is not synergistic with sulfamethoxazole. In addition, it was found that DHFR isolated from E. coli could be inhibited by sulfonamides, suggesting a multiple simultaneous inhibition of DHFR by both drugs. Curiously, it was also found that the TM potentiates sulfonamides that alone are resistant to the bacterium tested. 

MECHANISMS OF ANTIMALARIAL ACTION AND RESISTANCE The 2,4-diaminopyrimidines inhibit dihydrofolate reductase of plasmodia at concentrations far lower than those required to inhibit the mammalian enzymes. The dihydrofolate reductase in malaria resides on the same polypeptide chain as thymidylate synthase and is not upregulated in the face of inhibition, which contributes to the selective toxicity of the antifolates. Synergism between pyrimethamine and the sulfonamides or sulfones has been attributed to inhibition of two steps in an essential metabolic pathway. 

Aminosalicylic acid is a structural analog of pava-aminobenzoic acid, and has the same mechanism of action as the sulfonamides fsee Chapter 43). Nonetheless, the sulfonamides are ineffective against M. tuberculosis, and aminosalicylic acid is inactive against sulfonamide-susceptible bacteria. Resistant strains of tubercle bacilli emerge slowly in patients treated with aminosalicylic acid. 

Describe the mechanisms of antibacterial action of sulfonamides and trimethoprim on bacterial folic acid synthesis and the mechanisms involved in bacterial resistance to the antifolate drugs. 

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