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1.
Viruses ; 15(4)2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-37112867

RESUMO

Staphylococcus aureus causes intramammary infections (IMIs), which are refractory to antibiotic treatment and frequently result in chronic mastitis. IMIs are the leading cause of conventional antibiotic use in dairy farms. Phage therapy represents an alternative to antibiotics to help better manage mastitis in cows, reducing the global spread of resistance. A mouse mastitis model of S. aureus IMI was used to study the efficacy of a new cocktail of five lytic S. aureus-specific phages (StaphLyse™), administered either via the intramammary (IMAM) route or intravenously (IV). The StaphLyse™ phage cocktail was stable in milk for up to one day at 37 °C and up to one week at 4 °C. The phage cocktail was bactericidal in vitro against S. aureus in a dose-dependent manner. A single IMAM injection of this cocktail given 8 h after infection reduced the bacterial load in the mammary glands of lactating mice infected with S. aureus, and as expected, a two-dose regimen was more effective. Prophylactic use (4 h pre-challenge) of the phage cocktail was also effective, reducing S. aureus levels by 4 log10 CFU per gram of mammary gland. These results suggest that phage therapy may be a viable alternative to traditional antibiotics for the control of S. aureus IMIs.


Assuntos
Bacteriófagos , Mastite Bovina , Infecções Estafilocócicas , Feminino , Animais , Camundongos , Bovinos , Staphylococcus aureus , Lactação , Mastite Bovina/tratamento farmacológico , Mastite Bovina/microbiologia , Modelos Animais de Doenças , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Leite/microbiologia , Infecções Estafilocócicas/microbiologia
2.
Antibiotics (Basel) ; 12(6)2023 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-37370388

RESUMO

Prototypic Staphylococcus aureus and their small-colony variants (SCVs) are predominant in cystic fibrosis (CF), but the interdependence of these phenotypes is poorly understood. We characterized S. aureus isolates from adult CF patients over several years. Of 18 S. aureus-positive patients (58%), 13 (72%) were positive for SCVs. Characterization included genotyping, SCCmec types, auxotrophy, biofilm production, antibiotic susceptibilities and tolerance, and resistance acquisition rates. Whole-genome sequencing revealed that several patients were colonized with prototypical and SCV-related clones. Some clonal pairs showed acquisition of aminoglycoside resistance that was not explained by aminoglycoside-modifying enzymes, suggesting a mutation-based process. The characteristics of SCVs that could play a role in resistance acquisition were thus investigated further. For instance, SCV isolates produced more biofilm (p < 0.05) and showed a higher survival rate upon exposure to ciprofloxacin and vancomycin compared to their prototypic associated clones. SCVs also developed spontaneous rifampicin resistance mutations at a higher frequency. Accordingly, a laboratory-derived SCV (ΔhemB) acquired resistance to ciprofloxacin and gentamicin faster than its parent counterpart after serial passages in the presence of sub-inhibitory concentrations of antibiotics. These results suggest a role for SCVs in the establishment of persistent antibiotic-resistant clones in adult CF patients.

3.
Eur J Med Chem ; 262: 115886, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37924710

RESUMO

Antibiotic resistance is escalating alarmingly worldwide. Bacterial resistance mechanisms are surfacing and proliferating across the globe, jeopardizing our capacity to manage prevalent infectious illnesses. Without drastic measures, we risk entering a post-antibiotic era, where even trivial infections and injuries can cause death again. In this context, we have developed a new class of antibiotics based on tomatidine (TO), a natural product derived from tomato plants, with a novel mode of action by targeting bacterial ATP synthases. The first generation of compounds proved highly specific for small-colony variants (SCVs) of Staphylococcus aureus. However, optimization of this scaffold through extensive structure-activity relationship studies has enabled us to broaden its effectiveness to include both Gram-positive and Gram-negative bacteria. Notably, the results showed that specific C3-modification of TO could improve ATP synthase inhibition and also bypass the outer membrane barrier of Gram-negative bacteria to gain substantial growth inhibition including against multi-resistant strains.


Assuntos
Antibacterianos , Jardins , Antibacterianos/farmacologia , Antibacterianos/química , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Trifosfato de Adenosina
4.
Microbes Infect ; 24(1): 104879, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450272

RESUMO

Non-aureus staphylococci (NAS) and Staphylococcus aureus are pathogens that cause bovine mastitis, a costly disease for dairy farmers, however; many NAS are considered part of the normal udder microbiota. It has been suggested that through a mechanism that remains to be elucidated, NAS intramammary colonization can prevent subsequent infection with other bacterial pathogens. This study shows that in a murine mastitis model, secondary Staph. aureus intramammary colonization is reduced by exoproducts from Staph. chromogenes and Staph. simulans, both NAS, while Streptococcus spp. exoproducts have much less ability to affect the course of the infection caused by S. aureus.


Assuntos
Mastite Bovina , Infecções Estafilocócicas , Animais , Bovinos , Feminino , Glândulas Mamárias Animais/microbiologia , Mastite Bovina/microbiologia , Camundongos , Leite/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus , Staphylococcus aureus
5.
Front Microbiol ; 11: 805, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431678

RESUMO

Tomatidine (TO), a steroid alkaloid, exerts a strong bactericidal activity on the infection-persistent phenotype of Staphylococcus aureus, the small-colony variant (SCV), with a minimal inhibitory concentration (MIC) of 0.06 µg/ml. Also, the combination of TO to an aminoglycoside (AMG) shows a strong synergistic effect against prototypical (WT) S. aureus (MIC 0.06 µg/ml), which is otherwise unaffected by TO alone (MIC > 128 µg/ml). We have recently established that the ATP synthase (subunit AtpE) was the molecular target of TO and that TO reduces the production of ATP in S. aureus. The purpose of this study was to understand how TO and the TO-AMG combination exert bactericidal activities against S. aureus SCV and WT strains, respectively. The impact of TO and of the TO-gentamicin (GEN) combination on the membrane potential and generation of reactive oxygen species (ROS) were determined using florescent probes. GEN uptake in WT was assessed in the presence of TO. Virulence of SCV and WT strains as well as of in vitro-selected mutants showing resistance to TO or the TO-GEN combination was evaluated in a murine thigh infection model. TO causes a reduction in membrane potential in both WT and SCV, but significant amounts of ROS are only produced in SCVs. Besides, the presence of TO improves the uptake of GEN by the WT strain and the combination TO-GEN generated 2.5-folds more ROS in WT, compared to that induced by GEN alone. Under anaerobic conditions, WT adopts a fermentative slow-growth phenotype and becomes susceptible to TO even if used alone. In vivo, TO- or TO-GEN-resistant strains were significantly altered in their ability to colonize tissues. These results shed light on the mechanism of action of TO and its synergy with AMGs against S. aureus WT. TO bactericidal activity against SCVs is attributable to both a critical drop in the membrane potential accompanied by a substantial ROS production. In the WT, TO helps GEN uptake and ROS is also important for the synergy. Acquiring resistance to TO significantly impairs virulence. The residual ATP synthase activity of SCVs might represent the Achilles' heel of persistent S. aureus.

6.
Antimicrob Agents Chemother ; 47(2): 658-64, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12543674

RESUMO

RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 micro g/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC(50)) of 0.7 micro g/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC(50) of 0.8 micro g/ml and a MIC of 0.5 micro g/ml. The affinity of RWJ-54428 for PBPs of beta-lactam-susceptible S. aureus (MSSA), enterococci (E. hirae), and Streptococcus pneumoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A beta-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal beta-lactamases, including beta-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In summary, RWJ-54428 has high affinity to multiple PBPs and is stable to beta-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against beta-lactam-resistant gram-positive bacteria.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias , Proteínas de Transporte/farmacologia , Cefalosporinas/farmacologia , Enterococcus/efeitos dos fármacos , Hexosiltransferases , Muramilpentapeptídeo Carboxipeptidase/farmacologia , Peptidil Transferases , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Proteínas de Ligação às Penicilinas
7.
Bioorg Med Chem Lett ; 13(19): 3305-9, 2003 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-12951115

RESUMO

Dihydropacidamycins having an antibacterial spectrum modified from that of the natural product pacidamycins and mureidomycins have been synthesized. Synthetic dihydropacidamycins with noteworthy antibacterial activity against wild-type and resistant Escherichia coli have been identified (MIC=4-8 microg/mL). Some dihydropacidamycins are shown to have activity against multi-resistant clinical strains of Mycobacterium tuberculosis. Compounds of this class are inhibitors of the cell wall biosynthetic enzyme, MraY.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Peptídeos/síntese química , Peptídeos/farmacologia , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/farmacologia , Bactérias Aeróbias Gram-Negativas/efeitos dos fármacos , Bactérias Aeróbias Gram-Negativas/crescimento & desenvolvimento , Humanos
8.
Bioorg Med Chem Lett ; 12(5): 763-6, 2002 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-11858997

RESUMO

Several classes of peptidomimetics of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595) have been prepared and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin in Pseudomonas aeruginosa. A number of the new analogues were as active or more active than the lead, demonstrating that a peptide backbone is not essential for activity.


Assuntos
Anti-Infecciosos/farmacologia , Levofloxacino , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Ofloxacino/farmacologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Transporte Biológico Ativo/efeitos dos fármacos , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Mimetismo Molecular , Estrutura Molecular , Fragmentos de Peptídeos/química , Pseudomonas aeruginosa/fisiologia , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 13(23): 4241-4, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14623009

RESUMO

Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.


Assuntos
Anti-Infecciosos/farmacocinética , Transporte Biológico Ativo/efeitos dos fármacos , Diaminas/farmacocinética , Plasma/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Diaminas/administração & dosagem , Diaminas/farmacologia , Infusões Intravenosas , Metabolismo dos Lipídeos , Masculino , Testes de Sensibilidade Microbiana , Ofloxacino/metabolismo , Ofloxacino/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição Tecidual
10.
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