Sulfa and trimethoprim-like drugs – antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors

Abstract

Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families.

Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis

“…26,[39][40][41][42][43][44][45][46][47][48][49][50] Their biochemical features are known in detail for at least four classes, together with their distribution and role in various organisms. 32,33,41,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Inhibition and activation studies of many such enzymes from vertebrates, protozoa, fungi and bacteria have shown that they are drug targets for obtaining pharmacological agents of the diuretic, antiglaucoma, antiobesity, antiepileptic, anticancer or anti-infective type. [55][56][57][58]60 Many such enzymes also possess biotechnologic applications for biomimetic CO 2 capture processes.…”

“…4,5,[30][31][32][33][34][35][36][37][38] These enzymes are involved in a multitude of physiologic processes in organisms all over the phylogenetic tree, with six genetically distinct CA classes known to date: the a-, b-, c-, d-, f-and g-CAs. 26,[39][40][41][42][43][44][45][46][47][48][49][50] Their biochemical features are known in detail for at least four classes, together with their distribution and role in various organisms. 32,33,41,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Inhibition and activation studies of many such enzymes from vertebrates, protozoa, fungi and bacteria have shown that they are drug targets for obtaining pharmacological agents of the diuretic, antiglaucoma, antiobesity, antiepileptic, anticancer or anti-infective type.…”

“…5,23,[25][26][27][28][29][30]34,[36][37][38]42,44,[46][47][48][49][50] In the present paper, we describe the cloning, expression and purification of a c-CA identified in the genome of Pseudoalteromonas haloplanktis (formerly Alteromonas haloplanktis), which is an obligate aerobic gram-negative rod-like bacterium that was isolated from seawater sampled along the Antarctic ice shelf. This species thrives permanently in seawater at temperature ranging between +2°C and +4°C, being able to survive in frozen conditions for a long period, when entrapped in the winter ice pack.…”

The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932–2015)

“…Only hCA VB and especially hCA II, one of the best catalysts known in nature, show a better activity than HpbCA [38][39][40][41] . Also, it may be observed that the activity of all these enzymes is inhibited by the CA inhibitor (CAI) par excellence, the sulfonamide drug, acetazolamide AAZ [53][54][55][56][57] , which may explain why Ulcosilvanil showed a range of severe side effects, due to inhibition of CA isoforms in other organs than the stomach, or better to say, due to hCAs and not Hpa/bCA inhibition (Table 3).…”

Synthesis of N-alkyl (aril)-tetra pyrimidine thiones and investigation of their human carbonic anhydrase I and II inhibitory effects

“…They also help tumour growth by supplying HCO À 3 to be used as substrate for cell growth as this anion is required in the synthesis of pyrimidine nucleotides such as cytosine, thymine, and uracil 56 . Thus, specifically targeting the tumour-related isozymes (hCA IX and XII) over the main off target isoenzymes hCA I, and II may be a new antitumor approach, with a sulphonamide CA inhibitor in Phase I clinical trials for the treatment of hypoxic tumors [57][58][59] . However, CA II is also a drug target for antiglaucoma agents, diuretics and highaltitude sickness among others [60][61][62] .…”