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1.
J Med Microbiol ; 49(4): 339-342, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10755627

RESUMO

Mycobacterium leprae multiplies within host macrophages. The mechanism of internalisation of the bacteria by the phagocytic cells is unknown. In this study, M. leprae was purified from the foot pads of experimentally infected nu/nu mice. Peritoneal macrophages were harvested from BALB/c mice or C57 beige (bg/bg) mice. The effect of protein kinase inhibitors (erbstatin, genistein or staurosporine for BALB/c and bg/bg mice, plus herbimycin for bg/bg mice) on phagocytosis of the mycobacteria by the macrophage monolayers was tested. The untreated (control) macrophages phagocytosed M. leprae. Phagocytosis by BALB/c macrophages was inhibited by erbstatin and staurosporine but not by genistein; all the protein kinase inhibitors prevented uptake of M. leprae by bg/bg cells. The results demonstrate that protein kinase regulates phagocytosis of M. leprae by macrophages. The mechanism might prove to be a rational drug target for mycobacteria that multiply intracellularly.


Assuntos
Macrófagos Peritoneais/imunologia , Mycobacterium leprae/imunologia , Fagocitose/fisiologia , Proteínas Quinases/fisiologia , Animais , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Genisteína/farmacologia , Hidroquinonas/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Inibidores de Proteínas Quinases , Estaurosporina/farmacologia
2.
Int J Antimicrob Agents ; 13(2): 133-5, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10595573

RESUMO

The resistance of mycobacteria to beta-lactam antibiotics is attributed to their ability to synthesize beta-lactamase. In our previous studies, beta-lactam/beta-lactamase-inhibitor combinations suppressed the growth of several mycobacteria in axenic cultures and ampicillin/sulbactam was bactericidal to Mycobacterium tuberculosis H37Rv in vitro, and to Mycobacterium leprae multiplying in mouse foot-pads. Since both these organisms multiply in phagocytic cells in the host, it is important to know whether the drug combination is active against mycobacteria multiplying in macrophages. We tested the action of ampicillin/sulbactam against four potentially pathogenic (to humans or to animals) mycobacteria, M. simiae, M. haemophilum, M. avium, M. microti, when phagocytosed by mouse macrophages. Bacteria were exposed to monolayers of peritoneal macrophages harvested from BALB/c mice. Unphagocytosed bacilli were removed and three concentrations of ampicillin/sulbactam were tested. Optimum activity was observed at 100 mg/l which killed 58-97% of the mycobacteria within macrophages, as determined by the CFU. beta-Lactam/beta-lactamase-inhibitors, especially ampicillin/sulbactam, might provide an effective alternative therapy against infections caused by mycobacteria resistant to other drugs.


Assuntos
Ampicilina/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium/efeitos dos fármacos , Penicilinas/farmacologia , Sulbactam/farmacologia , Inibidores de beta-Lactamases , Animais , Contagem de Colônia Microbiana , Interações Medicamentosas , Humanos , Técnicas In Vitro , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium/crescimento & desenvolvimento , Fagocitose
3.
J Antimicrob Chemother ; 44(2): 279-81, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10473236

RESUMO

We reported previously that an injectable form of ampicillin/sulbactam, Unasyn, was bactericidal to Mycobacterium leprae multiplying in mouse foot pads. In this study, we examined the effect of an orally active form of ampicillin/sulbactam, Sultamicillin, on the growth of M. leprae in mice. Three concentrations of the drug, mixed with the feed, were administered from the start until the mice were killed at 6 months; 0.01% of the drug inhibited bacterial growth by 54%, 0.10% by 74% and 0.20% by 93%. To test whether oral ampicillin/sulbactam was bactericidal, 0.50% of the drug, mixed with the feed, was administered to experimentally infected mice for 3 months during the logarithmic phase of bacterial growth, and then discontinued; multiplication of the bacilli was monitored monthly for the next 8 months. The results showed that orally active ampicillin/sulbactam is bactericidal to M. leprae.


Assuntos
Quimioterapia Combinada/farmacologia , Mycobacterium leprae/efeitos dos fármacos , Administração Oral , Ampicilina/administração & dosagem , Ampicilina/farmacologia , Animais , Quimioterapia Combinada/administração & dosagem , Membro Posterior/microbiologia , Hanseníase/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Mycobacterium leprae/crescimento & desenvolvimento , Sulbactam/administração & dosagem , Sulbactam/farmacologia
5.
J Basic Microbiol ; 36(5): 341-9, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8914265

RESUMO

Lysophospholipids are key intermediates in the metabolism of phospholipids. Cytoplasmic membranes of both eukaryotes and prokaryotes are made of phospholipid bilayers. Phospholipases are activated during phagocytosis. Lysophospholipids generated by phospholipase A2 or A1 degrade cell membranes and can cause cell lysis. An active lysophospholipase, that hydrolyzes lysophospholipids, was detected by the radioisotope technique in Mycobacterium leprae. About two-thirds of the enzyme was particulate and one-third cytoplasmic. Optimum activity was at 37 degrees C, and at pH 6.0. Temperatures above 70 degrees C completely inactivated the enzyme. The compound AACOCF3, a trifluromethylketone analog of arachiodonic acid, inhibited the activity; the inhibition appeared to be of the uncompetetive type. The K(m) of the enzyme was 2.5 x 10(-4)M, suggesting a fairly strong affinity for the substrate. Lysophospholipids have been shown to be microbicidal to invading organisms. Possession of lysophospholipase by M. leprae is apparently one of the methods by which the bacilli overcome the defense mechanisms of the host.


Assuntos
Lisofosfolipase/metabolismo , Mycobacterium leprae/enzimologia , Ácidos Araquidônicos/farmacologia , Inibidores Enzimáticos/farmacologia , Concentração de Íons de Hidrogênio , Cinética , Lisofosfolipase/antagonistas & inibidores , Lisofosfolipídeos/metabolismo , Temperatura
8.
Microbios ; 76(309): 251-61, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8302203

RESUMO

Mycobacterium tuberculosis and Mycobacterium leprae develop resistance against the drugs used to treat tuberculosis and leprosy, respectively. Now multidrug-resistant tuberculosis is spreading in many countries, especially with the emergence of AIDS. Multidrug treatment is being promoted at present to eradicate leprosy. Since M. leprae may also become multidrug-resistant, new approaches have to be adopted for controlling mycobacterial diseases. Mycobacteria usually synthesize beta-lactamase and are insensitive to beta-lactam antibiotics. M. tuberculosis contains a constitutive beta-lactamase; de-repression of beta-lactamase has been reported in M. leprae. Three different beta-lactam/beta-lactamase-inhibitor combinations (ampicillin/sulbactam, amoxicillin/clavulanate and piperacillin/tazobactam) were used to suppress the growth of several strains of mycobacteria (including M. tuberculosis H37Rv) in vitro. Ampicillin/sulbactam is a potent bactericidal agent against M. leprae multiplying in mouse foot pads. In the present work, ampicillin/sulbactam showed higher activity than the other drug combinations. The beta-lactam/beta-lactamase inhibitors are likely to be effective as rational therapeutic agents against mycobacterial infections.


Assuntos
Antibacterianos/farmacologia , Quimioterapia Combinada/farmacologia , Mycobacterium/efeitos dos fármacos , Inibidores de beta-Lactamases , Amoxicilina/farmacologia , Combinação Amoxicilina e Clavulanato de Potássio , Ampicilina/farmacologia , Animais , Ácidos Clavulânicos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium/enzimologia , Mycobacterium/crescimento & desenvolvimento , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Sulbactam/farmacologia
9.
Microbios ; 70(283): 139-44, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1323745

RESUMO

Neurotropism is one of the unusual properties of Mycobacterium leprae. The organism contains glutamic acid decarboxylase that generates gamma-amino-butyric acid (GABA) which is an inhibitory neurotransmitter. The binding of GABA by M. leprae in vitro was studied by using 3H-GABA as substrate. The bacteria had high-affinity binding sites for the amino acid. The uptake was a specific saturable process with a Km of 66.7 pM, pH optimum of 7.3 and a temperature optimum of 37 degrees C. The binding did not seem to be time-dependent, being complete in about 5 min. None of the known antagonists and agonists of GABA uptake by neurons, showed any significant effect on M. leprae; the receptors in the bacteria are apparently of a non-neuronal type, and different from those reported in spermatozoa and Pseudomonas.


Assuntos
Mycobacterium leprae/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Tatus , Concentração de Íons de Hidrogênio , Cinética , Receptores de GABA-A/efeitos dos fármacos , Temperatura , Fatores de Tempo
10.
Microbios ; 72(291): 137-42, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1287401

RESUMO

The multiplication of Mycobacterium leprae in foot pads of experimentally-infected mice was suppressed by intramuscular administration of ampicillin combined with sulbactam or YTR-830H, two potent inhibitors of beta-lactamase in the bacteria. The antibiotic or the inhibitors by themselves were inactive. Ampicillin/sulbactam also inhibited the growth of drug-resistant M. leprae which grew in the presence of rifampin or dapsone. The finding provides a new approach to treat leprosy and to overcome drug resistance of the mycobacteria.


Assuntos
Ampicilina/farmacologia , Mycobacterium leprae/efeitos dos fármacos , Sulbactam/farmacologia , Animais , Resistência Microbiana a Medicamentos , Quimioterapia Combinada/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium leprae/crescimento & desenvolvimento
11.
Microbios ; 67(271): 125-32, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1833612

RESUMO

It is not known how Mycobacterium leprae obtains energy for survival and growth in the host tissues; the organism does not grow in vitro. In the studies reported here, M. leprae incorporated labelled ATP, which was blocked by cyanide, unlabelled ATP or ADP, but not by adenosine or Pi. It seems that the organism takes up unhydrolysed ATP by an active transport process. The bacterium contained a membrane-bound, vanadate-sensitive E1 E2-ATPase (which creates a transmembrane potential driving transport of solutes into cells). The enzyme was not inhibited by N-ethylmaleimide, suggesting that it is not an F0F1-ATPase which catalyses ATP synthesis. Apparently, M. leprae derives energy-rich compounds from the host cell.


Assuntos
Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Mycobacterium leprae/enzimologia , Vanadatos/farmacologia , Difosfato de Adenosina/farmacologia , Adenosina Trifosfatases/antagonistas & inibidores , Trifosfato de Adenosina/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Cianetos/farmacologia , Etilmaleimida/farmacologia , Concentração de Íons de Hidrogênio , Cinética , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/metabolismo
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