Pathways

Primaquine is an minoquinoline antimalarial is a radical cure and prevent relapse of vivax and ovale malarias following treatment with a blood schizontocide. It has also been used to prevent transmission of falciparum malaria by those returning to areas where there is a potential for re-introduction of malaria. It is the essential co-drug with chloroquine in treating all cases of malaria. In the blood, malaria parasites break down a part of the red blood cells known as haemoglobin. When this happens haemoglobin is divided into two parts; haem and globin. Haem is toxic to the malaria parasite. To prevent it from being damaged, the malaria parasite produces an chemical which converts the toxic haem into a non-toxic product. Primaquine acts by interfering with a part of the parasite (mitochondria) that is responsible for supplying it with energy. Without energy the parasite dies. Primaquine's mechanism of action is not well understood. It may be acting by generating reactive oxygen species or by interfering with the electron transport in the parasite. Also, although its mechanism of action is unclear, primaquine may bind to and alter the properties of protozoal DNA.

Teicoplanin is a glycopeptide antibiotic with a similar mechanism of action and spectrum of activity to vancomycin used to treat various infections caused by gram-positive bacteria. It is used for the treatment of bacterial infections caused by susceptible microorganisms. It is a glycopeptide antiobiotic extracted from Actinoplanes teichomyceticus, with a similar spectrum of activity to vancomycin. Its mechanism of action is to inhibit bacterial cell wall synthesis. Teicoplanin inhibits peptidoglycan polymerization, resulting in inhibition of bacterial cell wall synthesis and cell death. Oral teicoplanin has been demonstrated to be effective in the treatment of pseudomembranous colitis and Clostridium difficile-associated diarrhoea, with comparable efficacy to vancomycin. Teicoplanin is poorly absorbed after oral administration but is 90% bioavailable when administered intramuscularly.

Vidarabine is an antiviral agent used to treat various viral infections. It has some antineoplastic properties and has broad spectrum activity against DNA viruses in cell cultures and significant antiviral activity against infections caused by a variety of viruses such as the herpes viruses, the vaccinia VIRUS and varicella zoster virus. Vidarabine stops replication of herpes viral DNA by either competitive inhibition of viral DNA polymerase, and consequently or incorporation into and termination of the growing viral DNA chain. Vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP, which is the active form of vidarabine that acts as both an inhibitor and a substrate of viral DNA polymerase.Ara-ATP inhibits the activity of DNA polymerase by competing with its substrate dATP. Ara-ATP also gets incorporated into viral DNA, but since it lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, this causes DNA chain termination, preventing the growth of viral DNA.

Dalbavancin is an antibacterial used to treat acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible strains of Gram-positive bacteria. Dalbavancin is a second-generation lipoglycopeptide antibiotic that was designed to improve on the natural glycopeptides currently available, such as vancomycin and teicoplanin. Dalbavancin has a spectrum and mechanism of action similar to vancomycin, a naturally formed glycopeptide antimicrobial. The bactericidal action of dalbavancin results primarily from inhibition of cell-wall biosynthesis. Specifically, dalbavancin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, which is normally a five-point interaction. Binding of dalbavancin to the D-Ala-D-Ala prevents the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. In addition, dalbavancin alters bacterial-cell-membrane permeability and RNA synthesis. Dalbavancin for injection is indicated for the treatment of adult patients with ABSSSI, caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus) and Enterococcus faecalis (vancomycin susceptible strains). Dalbavancin is not active against gram-negative bacteria.

Telavancin is an antibacterial agent used in the treatment of complicated skin and skin structure infections and types of hospital-acquired bacterial pneumonia. Telavancin is a semi-synthetic derivative of vanocymycin that has bactericidal activity against Methicillin-resistant Staphylococcus aureus (MRSA) and other gram-positive bacteria. It is used for the treatment of complicated skin and skin structure infections (cSSSI) caused by gram-positive bacteria like methicillin-susceptible or -resistant Staphylococcus aureus, vancomycin-susceptible Enterococcus faecalis, and Streptococcus pyogenes, Streptococcus agalactiae, or Streptococcus anginosus group. It is also used for the treatment of adult patients with hospital-acquired bacterial pneumonia (HAP) and ventilator-associated bacterial pneumonia (VAP), known or suspected to be caused by susceptible isolates of Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant S. aureus). Telavancin prevents polymerization of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) and cross-linking of peptidoglycan by binding to D-Ala-D-Ala. As a result, inhibition of bacterial cell wall synthesis occurs. Furthermore, telavancin disrupts membrane potential and cell permeability as a result of the lipophillic side chain moiety. This additional bactericidal mechanism is what sets telavancin apart from vancomycin.

Edoxudine is a deoxythymidine analog used to treat herpetic keratitis. Edoxudine was used in Europe, in the form of a topical antiviral, for the treatment of human herpes keratitis. Human herpes keratitis is an inflammation of the cornea in the eye caused by herpes simplex virus infection. This infection is a cause of significant morbidity whose incidence is significantly increased in the presence of recurrent infection and it can even produce corneal blindness. Edoxudine is a potent inhibitor of the replication of herpes simplex virus type 1 and 2. For the activation of this drug, the action of viral thymidine kinase is required to phosphorylate this molecule in order to form the 5'-monophosphate derivative. Then, it is needed to be further phosphorylated by cellular enzymes until the formation of the 5'-triphosphate derivative which is a competitive inhibitor of the viral-coded DNA polymerase. Edoxudine 5'triphosphate inhibits the activity of DNA polymerase by competing with its substrate dGTP. Acyclovir triphosphate also gets incorporated into viral DNA, but since it lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, this causes DNA chain termination, preventing the growth of viral DNA. Less Viral DNA is transported into the nucleus, therefore, less viral DNA is integrated into the host DNA. Less viral proteins produced, fewer viruses can form.

Ganciclovir is a DNA polymerase inhibitor used to treat cytomegalovirus and herpetic keratitis of the eye in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). It is also be used to treat severe cytomegalovirus (CMV) disease, such as CMV pneumonia, CMV gastrointestinal disease, and disseminated CMV infections. Ganciclovir's antiviral activity inhibits virus replication. This inhibitory action is highly selective as the drug must be converted to the active form by a virus-encoded cellular enzyme, thymidine kinase, which catalyzes phosphorylation of ganciclovir to ganciclovir monophosphate. Ganciclovir monophosphate is converted into the diphosphate by cellular guanylate kinase then into the triphosphate by a number of cellular enzymes. Ganciclovir triphosphate inhibits the activity of DNA polymerase by competing with its substrate dGTP. Ganciclovir triphosphate also gets incorporated into viral DNA, but since it lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, this causes DNA chain termination, preventing the growth of viral DNA. Less Viral DNA is transported into the nucleus, therefore, less viral DNA is integrated into the host DNA. Less viral proteins produced, fewer viruses can form.

Penciclovir is a topical nucleoside polymerase inhibitor used in the treatment of various herpes simplex virus (HSV) infections. Penciclovir has in vitro activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1 or HSV-2, viral thymidine kinase phosphorylates penciclovir to a monophosphate form. The monophosphate form of the drug is then converted to penciclovir triphosphate by cellular kinases. Penciclovir triphosphate inhibits the activity of DNA polymerase by competing with its substrate dGTP. Less Viral DNA is transported into the nucleus, therefore, less viral DNA is integrated into the host DNA. Less viral proteins produced, fewer viruses can form.

Cidofovir is an injectable antiviral agent used to treat Cytomegalovirus (CMV) retinitis in patients with AIDS. It was manufactured by Gilead and initially approved by the FDA in 1996, but has since been discontinued. Cidofovir acts through the selective inhibition of viral DNA polymerase. After incorporation into the host cell, cidofovir is phosphorylated by pyruvate kinases to the active metabolite cidofovir diphosphate. Cidofovir diphosphate inhibits herpesvirus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerase alpha, beta, and gamma(1,2,3). Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis. Less Viral DNA is transported into the nucleus, therefore, less viral DNA is integrated into the host DNA. Less viral proteins produced, fewer viruses can form.

Famciclovir is a nucleoside analog DNA polymerase inhibitor used for the treatment of recurrent cold sores and genital herpes in healthy patients and patients with HIV, and to manage herpes zoster. Famciclovir undergoes rapid biotransformation to the active antiviral compound penciclovir, which has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). Famciclovir is hydrolyzed into Desacetylfamciclovir which is hydrolyzed into 6-Deoxypenciclovir. 6-Deoxypenciclovir is then oxidated into Penciclovir. This is transported by drug transporters into the blood then to the infected cell. Viral thymidine kinase phosphorylates penciclovir to a monophosphate form. The monophosphate form of the drug is then converted to penciclovir triphosphate by cellular kinases.Penciclovir triphosphate inhibits the activity of DNA polymerase by competing with its substrate dGTP. Less Viral DNA is transported into the nucleus, therefore, less viral DNA is integrated into the host DNA. Less viral proteins produced, fewer viruses can form.