Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications.

Teratogenic Agents

This chapter reviews background information about the incidence and epidemiology of common teratogenic agents, including prescription medications and congenital infections such as LCMV, parvovirus, TORCH, syphilis, and Zika. The characteristic fetal effects of in utero exposure to ACE inhibitors, anticoagulants, anticonvulsants, folic acid antagonists, immunosuppresants, and Vitamin A derivatives are reviewed. The teratogenic effects associated with chronic maternal disorders, such as gastric bypass surgery, hyperemesis gravidarum, hypertension, hyperthyroidism, and maternal phenylketonuria are discussed. The differential diagnosis includes Mendelian disorders with similar phenotypes. The chapter includes recommendations for evaluation and management. A clinical case presentation features an infant with first-trimester exposure to misoprostol (Cytotec).

Synergistic Antimicrobial Activities of Folic Acid Antagonists and Nucleoside Analogs

ABSTRACT The antimicrobial activities of folic acid antagonists are supposed to be antagonized by elevated extracellular thymidine concentrations in damaged host tissues. Therefore, this study was aimed at screening for nucleoside analogs that impair bacterial thymidine utilization and analyzing the combined antimicrobial activities of nucleoside analogs and folic acid antagonists in the presence of thymidine. Our screening results revealed that different nucleoside analogs, in particular halogenated derivatives of 2′-deoxyuridine, substantially impaired the bacterial utilization of extracellular thymidine in Staphylococcus aureus. Time-kill methods showed that 5-iodo-2′-deoxyuridine enhanced the extent of killing of trimethoprim-sulfamethoxazole (SXT) at 24 h against S. aureus in the presence of thymidine (200 μg/liter). While SXT (40 mg/liter) alone did not kill bacteria in the presence of thymidine, its combination with the nucleoside analog at a concentration of 8 μmol/liter showed a bactericidal effect. Moreover, 5-iodo-2′-deoxyuridine combined with SXT in the presence of thymidine showed a broad spectrum of activity against several Gram-positive and Gram-negative bacteria. In conclusion, these data provide evidence that the in vitro antimicrobial activity of SXT in the presence of thymidine can be significantly improved by combination with a nucleoside analog.