Other protein synthesis inhibitors Lincosamides and Streptogramins and

1. Other protein synthesis inhibitors Lincosamidesand Streptograminsand RNA polymerase inhibitor Rifampicin by Dr. Ibtesam G. Auda

2. Lincosamides lincosamideclass of antibacterials originates from a natural product, lincomycin, and includes semisynthetic derivatives, clindamycin and pirlimycin. The first lincosamide to be discovered is lincomycin, isolated from Streptomyces lincolnensis in a soil sample from Lincoln, Nebraska (hence the bacterial name). This class was first characterized in the 1960s and is now used for treatment of a broad spectrum of infections. It is mostly active against gram-positive organisms, but also finds use against selected gram-negative anaerobes and protozoa.

4. Mode of action These antibiotics function by blocking microbial protein synthesis via binding to the 23S rRNA of the 50S subunit and mimicking the intermediate formed in the initial phase of the elongation cycle

5. Spectrum of activity Usage of lincomycin has been largely superseded by clindamycin which exhibits improved antibacterial activity. Clindamycin also exhibits some activity against parasitic protozoa and has been used for toxoplasmosis and malaria. Lincosamides are normally used to treat Staphylococcus and Streptococcus and have proved useful in treating Bacteroidesfragilis and some other anaerobes. They are used in the treatment of toxic shock syndrome and thought to directly block the M protein production that leads to the severe inflammatory response. Lincosamide antibiotics are one of the classes of antibiotics most associated with pseudomembranous colitis caused by Clostridium difficile.

6. resistance increased antibiotic use leads to the development of resistance. Two of the most common routes of resistance to lincosamides include Antibiotic modification, a route more prevalent in pathogenic gram-positive cocci, Organisms employing the antibiotic modification strategy inactivate lincosamides via adenylylation catalyzed by enzymes encoded by lingenes. These enzymes show amino acid sequence homology with the aminoglycoside antibiotic nucleotidyltransferase Methylation of the ribosomal 23S rRNAby Ermmethyltransferases, observed in many genera and resulting in coresistance to macrolide and type B streptogramin antibiotics.

7. Lincomycin Lincomycin is used for treating serious bacterial infections caused by susceptible strains of streptococci, pneumococci, and staphylococci. Use of lincomycin is reserved for penicillin-allergic patients or when penicillin-based treatment is not appropriate. This antibiotic should only be used to treat serious infections because of rare but sometimes fatal intestinal problems have occurred (pseudomembranous colitis). SIDE EFFECTS: Side effects of lincomycin are: nausea, vomiting, diarrhea, abdominal pain, rash, and itching.

8. clindamycin The most clinically relevant lincosamide, clindamycin, is frequently used to treat infections caused by streptococci and staphylococci. It is particularly useful in treatment of connective tissue infections because of its favorable skin and bone absorptivity and action against strains producing necrotizing toxins. Clindamycin treatments have been limited in the past because of rapid development of resistance and gastrointestinal side effects. Recently, as the emergence of multidrug-resistant pathogens has become a grave concern, lincosamide use has been revisited. In particular, clindamycin has been found to be potent in treating methicillin-resistant Staphylococcus aureus (MRSA), a pathogen causing worldwide concern because of its increasing rate of incidence and limited treatments This drug is available in many forms. It comes as an oral capsule, oral solution, topical foam, topical gel, topical lotion, topical swab, topical solution, vaginal suppository, and vaginal cream. It’s also available as an intravenous (IV) drug

9. Streptogramins Streptograminsirreversibly  bind to the 50S ribosomal subunit.  Group Astreptogramins prevent peptide bond formation during chain elongation step, while group B components cause the release of incomplete peptide chains from the 50S ribosomal subunit. Streptogramins are effective in the treatment of vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin-resistant Enterococcus (VRE), two of the most rapidly growing strains of multidrug-resistant bacteria. They fall into two groups: streptogramin A and streptogramin B. Members include: Quinupristin/dalfopristin Pristinamycin Virginiamycin NXL 103, an experimental streptogramin in clinical trials for the treatment of respiratory tract infections

10. Rifampicin Rifampicin, also known as rifampin is made fromAmycolatopsisrifamycinicais an antibiotic used to treat a several types of bacterial infections. This includes tuberculosis, leprosy, and Legionnaire's disease. It is almost always used along with other antibiotics, except when given to prevent Haemophilusinfluenzae type b and meningococcal disease in those who have been exposed to those bacteria.

11. Mechanism of action Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase. Crystal structure data and biochemical data suggest that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and prevents RNA synthesis by physically blocking the formation of the phosphodiester bond in the RNA backbone, preventing extension of RNA more than 2 to 3 nucleotides Binding of rifampicin in the active site of RNA polymerase. Mutation of amino acids shown in red are involved in resistance to the antibiotic.

12. Spectrum of activity Rifampicin is used for the treatment of tuberculosis in combination with other antibiotics, such as pyrazinamide, isoniazid, and ethambutol. For the treatment of tuberculosis, it is administered daily for at least 6 months. Combination therapy is utilized both to prevent the development of resistance and to shorten the length of treatment.Resistance of Mycobacterium tuberculosis to rifampicin develops quickly when it is used without another antibiotic Rifampicin can be used alone in patients with latent tuberculosis infections to prevent the development of active disease because only small numbers of bacteria are present.   Rifampicin is also used to treat non-tuberculousmycobacterial infections including leprosy (Hansen's disease) and Mycobacterium kansasii Rifampicin is sometimes used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid, including in difficult-to-treat infections such as osteomyelitis and prosthetic joint infections. It is also used as preventive treatment against Neisseria meningitidis (meningococcal) infections. contraindicated, such as in pregnant women or in patients with a history of allergy to tetracycline antibiotics.

13. It is also sometimes used to treat infections by Listeria species, Neisseria gonorrhoeae, Haemophilusinfluenzae, and Legionella pneumophila. For these nonstandard indications, antimicrobial susceptibility testing should be done (if possible) before starting rifampicin therapy. The Enterobacteriaceae, Acinetobacter species, and Pseudomonas species are intrinsically resistant to rifampicin. It has been used with amphotericin B in largely unsuccessful attempts to treat primary amoebic meningoencephalitis caused by Naegleriafowleri. Rifampicin can be used as monotherapy for a few days as prophylaxis against meningitis, but resistance develops quickly during long-term treatment of active infections, so the drug is always used against active infections in combination with other antibiotics. Rifampicin has some effectiveness against vaccinia virus

14. Mechanism of resistance Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin. Resistance mutations map to the rpoB gene, encoding the beta subunit of RNA polymerase. The majority of resistance mutations in E. coli are in 3 clusters on rpoB. InMycobacterium tuberculosis, the majority of mutations leading to rifampicin resistance are in cluster I.

15. Resistance in tuberculosis Mycobacterial resistance to rifampicin may occur alone or along with resistance to other first line anti-tubercular drugs. Early detection of such multi-drug or extensively drug-resistant tuberculosis is critical in improving patient outcomes by instituting appropriate second-line treatments, and in decreasing transmission of drug-resistant TB.

16. Adverse effects The most serious adverse effect is hepatotoxicity.Themore common side effects include fever, gastrointestinal disturbances, rashes, and immunological reactions. Taking rifampicin usually causes certain bodily fluids, such as urine, sweat, and tears, to become orange-red in color, This may also be used to monitor effective absorption of the drug (if drug color is not seen in the urine, the patient may wish to move the drug dose farther in time from food or milk intake). Other adverse effects include: Liver toxicity — hepatitis, liver failure in severe cases Respiratory — breathlessness Cutaneous — flushing, pruritus, rash, hyperpigmentation, redness and watering of eyes Abdominal — nausea, vomiting, abdominal cramps, diarrhea Flu-like symptoms — chills, fever, headache, arthralgia, and malaise. Rifampicin has good penetration into the brain, and this may directly explain some malaise and dysphoria in a minority of users. Allergic reaction — rashes, itching, swelling of the tongue or throat, severe dizziness, and trouble breathing