Antimicrobials 2

Antiviral drugs inhibit virus replication by targeting specific viral proteins. Resistance develops through mutation of the target protein. Because viruses replicate inside host cells using host machinery, finding viral-specific targets for antiviral drugs is more challenging than for antibacterial drugs, and antiviral drugs tend to have narrower spectra.

For HIV, antivirals target multiple steps of the replication cycle. CCR5 inhibitors (e.g., maraviroc) block co-receptor binding. Fusion inhibitors (e.g., enfuvirtide) prevent gp41-mediated membrane fusion. Reverse transcriptase inhibitors (RTIs) block reverse transcription of viral RNA to DNA. Integrase inhibitors prevent viral DNA integration into the host genome. Protease inhibitors prevent processing of the viral polyprotein. Combination antiretroviral therapy (cART) uses drugs from multiple classes to prevent resistance.

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are treated with acyclovir, a deoxyguanosine nucleoside analogue. In virus-infected cells, viral thymidine kinase phosphorylates acyclovir to its monophosphate form; cellular kinases add further phosphates. The triphosphate form is incorporated into viral DNA, causing chain termination. Acyclovir has high selectivity because viral thymidine kinase is far more efficient at phosphorylating it than cellular kinases. Ganciclovir (activated by CMV phosphotransferase) treats cytomegalovirus (CMV) infections in immunocompromised patients. Oseltamivir and zanamivir are neuraminidase inhibitors used against influenza A and B.

Antifungal drugs target ergosterol (the primary sterol in fungal cell membranes, analogous to cholesterol in human cells) or the fungal cell wall. Polyenes (e.g., amphotericin B) bind ergosterol and form membrane channels causing cation leakage. Azoles (fluconazole, itraconazole) inhibit 14-alpha-demethylase, an enzyme in the ergosterol biosynthesis pathway. Echinocandins (e.g., caspofungin) target beta-(1,3)-glucan synthase, inhibiting fungal cell wall synthesis, analogous in principle to beta-lactams in bacteria. Terbinafine (allylamine) inhibits an earlier step in ergosterol synthesis (squalene monooxygenase) and is useful for cutaneous and nail infections.