evropský sociálny MINISTERSTVO ŠKOLSTVÍ fond v CR EVROPSKÁ UNIE mládeže a tělovýchovy i. OP Vzdělávání pro konkurenceschopnost INVESTICE DO ROZVOJE VZDĚLÁVÁNÍ Antituberculotics and antileprotics ©Oldřich Farsa 2012 TBC and lepra •tuberulosis (consumption; TBC) - WHO report: 2.109 infected in 2009 •leprosy (Hansen disese, hanseniasis) - approx. 1.2 . 106 infected in 2000, number of novel cases was 296 499 in 2005 •causing microorgansims: namely Mycobacterium tuberculosis, M. leprae •also M. bovis and so called atypical strains (or facultatively pathogenic strains): Mycobacterium avium, M. intracellular, M. kansasii, M. paratuberculosis, M. scrofulaceum, M. simiae, M. habana, M. interjectum, M. xenopi, M. heckeshornense, M. szulgai, M. fortuitum, M. immunogenum, M. chelonae, M. marinum, M. genavense, M. haemophilum, M. celatum, M. conspicuum, M. malmoense, M. ulcerans, M. smegmatis, M. wolinskyi, M. goodii, M. thermoresistible, M. neoaurum, M. vaccae, M.palustre, M. elephantis, M. bohemicum and M. septicum. •slowly growing bacteria with a special cell wall structure; most of common antibacterial chemotherapeutics are ineffective •the cell wall contains proteins, phenolic glycolipids, arabinoglycan, pepdidoglycan and mycolic acids (branched a-hydroxylated long-chain fatty acids; some containing cyclopropane fragment) •cultivation of M. tuberculosis in vitro is difficult, cultivation of M. leprae in vitro is impossible •M. tuberculosis discovered Robert Koch in 1882, M. leprae G. H. A. Hansen in 1874 •leprosy is quite endemic, most of infected live in 11 countries, India is leading, •"classical therapy" before discovery of effective chemotherapeutics: TBC -mountain environment, pneumothorax, Ca2+ compounds (calcification); leprosy -isolation of patients only - leprosaria Structures of mycolic acids and their appearance in some species of Mycobacterium genus oxygenated mycolatcs 1st used specific chemoterapeutics HO^O HoN 4-amino-2-hydroxybenzoic acid p-aminosalicylic acid PAS 4,4'-sulfonyldianiline 1 ,r-bis(4-aminophenyl)sulfone 1,1 '-sulfonylbis(4-aminobenzene) 4,4'-diaminodiphenyl sulfone dapson TBC leprosy Classification of chemotherapeutics of mycobacterial infections „Specific" chemoterapeutics PAS Compouns derived from sulfonamides Amides, hydrazide s and thioamides of heteroarenecarboxylic acids 1,2-diaminoethane derivatives Thiacetazone Tiocarlide Phenazine derivatives (Phenothiazines) Peptide antibiotics Broad spectrum chemoterapeutics Rifamycins Aminoglycosides Cycloserin Fluorinated quinolons Tetracyclins Macrolides Oxazolidine-2-on derivatives „Specific" chemoterapeutics PAS •1946: inhibits growth of mycobacteria even in dilution 1 : 105 in vitro •low toxicity enabled high doses 10-15 g/day •stability: easily decarboxylates to 2-aminophenol in acid media •metabolism: N-acetylation preferred •bacteriostatic effect •mode of action: dihydropteroate synthase inhibition (like sulfonamides) O OH 4-acetamido-2-hydroxybenzooic acid, main PAS metabolit OH O Compounds derived from sulfonamides structure Dapson H2N •prepared by Fromm and Wittmann in 1908 • antibacterial effects including antimycobacterial ones were discovered approx. in 1937, but originally was dapson supposed to be too toxic, after changed in dosing, it has been frequently used since 1940th. •mode of action: inhibition of folic acid synthesis, inhibition of dihydropteroate synthase (like sulfonamides) in particular •also drug for malaria (in combinations) and skin infections including acne vulgaris and diseases linked with the excessive accumulation of neutrophils and eosinophils, also lupus erythematodes, psoriasis and ulcers after intoxication by a spider of Loxosceles genus •adverse effects: methaemoglobinema, hemolysis, anaemia, agranulocytosis, nausea, vomitting, peripherial neuropathy, psychosis, rarely reversible eye disorders, photosensitivity Amides, hydrazides and thioamides of heteroarencarboxylic acids O NH NH. N pyrazinamide pyrazine-2-carboxamide •strong synergy with isoniazid and rifampicin •enabled shorten the treatment from initial 12 months or more to 6 months •effect is dependent on the presence of bacterial amidase; pyrazinic acid (pyrazin-2-carboxylic acid) is its active form. •Meningitis tuberculosa Pyrazinamid Krka ® tbl. isoniazid pyridine-4-carbohydrazide •known since 1912, effect recognized in 1951 •effective in vitro even in dilution 1 : 107 (or MIC 0.02-0.06 jig/ml) •mechanism of action: blocks mycolic acids synthesis by inhibition of mycolate synthetase and thus blocks cell wall building Nidrazid ® tbl. Amides, hydrazides and thioamides of heteroarencarboxylic acids 2-alkylpyridine-4-karbothioamides ethionamide prothionamide •mechanism of action: block synthesis of mycolic acids by inhibition of mycolate synthetase and thus block cell wall building 1,2-diaminoethane derivatives (S,S')-N,N'-bis(1-hydroxybutane-2-yl)ethylenediamine (+)-ethambutol •(R,R)- a (R,S)- isomers are not effective •used as dihydrochloride •bacteriostatic •mechanism of action: inhibits arabinosyl transferase which takes part in cell wall biosynthesis •used since 1966 •administered always in combinations (e.g. with isoniazide or rifampicin) due to a risk of development of resistant mutants •interaction with antacids based on AI(OH)3 •toxicity: damage of visual nerve •preparation from (S)-(+)-2-aminobutanol which is acquired by dividing of its racemate by crystallisation with tartaric acid Sural ®tbl. Thioacetazone HoN 4-(acetamido)benzaldehyde thiosemicarbazone •syn. thiacetazone •bacteriostatic effect •activated by mycobacterial monooxygenase EthA •mechanism of action: inhibition of mycolic acids synthesis; probably by blocking of cyclopropanation of mycolic acids by inhibition of cyclopropane mycolic acid synthases (CMASs). •combined with isoniasid •cheap; used in Africa and Southern America Tiocarlide 1,3-bis[4-(3-methylbutyloxy)phenyl]thiourea 4,4'-bis(isopentyloxy)thiokarbanilide •syn. isoxyl •mechanism of action: inhibition of membrane-bound A9 desaturase DesA3 => inhibition of syntheses of oleic acid and mycolic acids •used in 1960th, then abandoned, after 2000, its efficacy against multiresistant strains was demonstrated and its mechanism of action was determined and it has started to be used again Phenazine derivatives ci CI clofazimine •dye •leprosy •also anti-inflammatory effect •treatment of erythema nodosum leprosum Lamprene ® por cps dur ci BM 4169 •greater activity against M. tuberculosis including multiresistant strains Phenothiazine derivatives CH 10-[2-(N-methyl-2-piperidyl)ethyl]-2-methylsulfanylphenothiazin thioridazine (normally used as an antipsychotic) Supposed mechanisms of antituber. action: 1. calmoduline antagonist; genes of calmoduline type were found in M. tuberculosis, penothiazines are in general known by their calmoduline antagonist activity 2. phenothiazines inhibit succinate dehydrogenase and NADH-quinone oxidoreductase type II, cause depletion of ATP levels and change ratios NADH/NAD and menaquinol/menaquinone, which indicates an interference with oxidative phosphorylation •expected usage in multiresistant strains Peptide antibiotics H viomycin capreomycin •product of Streptomyces puniceus .product of Steptomyces capreolus •strongly basic peptides •mechanismm of action: bound to RNA, they inhibit protheosynthesis and some types of splicing of RNA •nephrotoxicity, neurotoxicity, ototoxicity, alergenicity Broad spectrum antibacterial chemoterapeutics used for treatment of mycobakterioses Rifamycins ?H3 9H3 R -CH rifampicin Arficin ® cps., Benemycin ® cps., Eremfat i.v. ® inj. plv. sol. rifapentine •mechanism of action: inhibition of DNA-dependent RNA polymerase Rifamyciny rifabutin CH3 M. avium-intracellulare Mycobutin cps. Aminoglycosides of the 1 line HO,. N-methyl-L-glukosamine HO R H streptidine = aglycone O OH OH CH •1 really active antituberculotic •R = -CHO streptomycin •used against M. tuberculosis in combination with other tuberculostatics •isolated from Streptomyces fradiae in 1944 •bactericidal •toxicity in both central and peripheral nervous system •Streptomycin „Grunenthal"® inj. sic, Streptowerfft® a.u.v •R = -CH2OH dihydrostreptomycin •formerly believed to be less toxic, however, damages 8th cranial nerve •Depomycine® a.u.v. inj. (+ benzylpenicillin) •mechanism of action: protheosynthesis inhibition Aminoglycosides of 2nd line HO H2N OH H2N R = -H O R = OH kanamycin amikacin •mechanism of action: bound to the 30S subunit of a ribosome, they cause wrong reading of mRNA and thus block protheosynthesis •serious multiresistantn infections •damage kidneys and sense of hearing Cycloserine H H2N (4R)-4-amino-1,2-oxazolidin-3-one D-cycloserine •antibiotic originally produced by Streptomyces garyphalus. •mode of action: blocks cell wall building by inhibition of early stage peptidoglycane biosynthesis •adverse effects: CNS: headaches, irritation, depression, convulsions Fluorinated quinolones R/S: Ofloxacin trovafloxacin Floxal(r) S: levofloxacin Tavanic i.v.(r) inf sol Fluorinated quinolones - continued gatifloxacin moxifloxacin 1 -Ethyl-6-fluoro-1,4-dihydro-4- Avelox ® por tbl flm, inf sol oxo-7-(1 -piperazinyl)-1,8- naphthyridine-3-carboxylic acid •mechanism of action: bacterial topoisomerase II (gyrase) and IV inhibition •high incidence of resistance - usage only based on the determined susceptibility Tetracyclins minocycline •efficient to some strains of M. tuberculosis, leprae, avium... •in combinations (rifampicin, ofloxacin ...) •restoring to health from tuberculoid leprosy - single skin lesion by single dose administration has been referred •mechanism of action: protheosynthesis inhibition Skid® Macrolides O claritromycin •against M. avium complex in patients with HIV •bacteriostatic •mechanism of action: inhibition of protheosynthesis - translation by binding to 50S ribosome subunit Oxazolidin-2-one derivatives 0-R X = S U-100480 R = -P=0(OH)2 DA-7218 X = 0 linezolid R =-H DA-7157 •against multiresistant strains of M. tuberculosis •mechanism of action: protheosynthesis inhibition by different way than other known antibacterial chemotherapeutics: bound to 23S subunit rRNAthey inhibit the early stage of translation by preventing of correct binding of formyl-methionine tRNA •they inhibit protheosynthesis also in mammal mitochondrias myelosupression, peripheral neuropathy as important adverse effects