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1.
Artigo em Inglês | MEDLINE | ID: mdl-31208999

RESUMO

Levonadifloxacin is a novel benzoquinolizine subclass of fluoroquinolone, active against quinolone-resistant Staphylococcus aureus A phase 3 trial for levonadifloxacin and its oral prodrug was recently completed. The present study identified area under the concentration-time curve for the free, unbound fraction of a drug divided by the MIC (fAUC/MIC) as an efficacy determinant for levonadifloxacin in a neutropenic murine lung infection model. Mean plasma fAUC/MIC requirement for static and 1 log10 kill effects against 9 S. aureus were 8.1 ± 6.0 and 25.8 ± 12.3, respectively. These targets were employed in the selection of phase 3 doses.

2.
J Med Microbiol ; 68(8): 1129-1136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31241446

RESUMO

PURPOSE: Staphylococcus aureus causes a wide range of infections, such as endocarditis, pneumonia, osteomyelitis, skin and soft tissue infections, and implant/in-dwelling device-related infections. S. aureus poses a significant challenge to clinicians because of its ability to rapidly acquire multi-drug resistance and quickly progress into a recurrent, chronic infection by biofilm formation. Levonadifloxacin (WCK 771) is a novel broad-spectrum antibacterial agent (it recently completed a phase 3 trial in India) with a differentiated mechanism of action involving high affinity to staphylococcal DNA gyrase, and is active against multi-drug-resistant (MDR) S. aureus, including those that are resistant to quinolones. The present study investigated the bactericidal activity of levonadifloxacin against biofilm-embedded S. aureus clinical isolates in comparison with other anti-S. aureus drugs. METHODOLOGY: The bactericidal activity of levonadifloxacin and comparator drugs such as vancomycin, linezolid and daptomycin was evaluated against planktonic and biofilm-encapsulated recent methicillin- and quinolone-resistant S. aureus clinical isolates using time-kill, biofilm eradication and scanning electron microscopy analysis. RESULTS: Levonadifloxacin displayed a consistent ≥90 % bacterial kill rate against biofilm-embedded organisms, while vancomycin and linezolid displayed variable activity and daptomycin did not show any activity. Scanning electron microscopy images further confirmed the efficacy of levonadifloxacin against biofilm, showing the disruption of biofilm structure and a corresponding reduction in the viable bacterial count. CONCLUSION: These results show that levonadifloxacin has an improved bactericidal effect on biofilm-embedded quinolone-resistant S. aureus and meticillin-resistant S. aureus, and that it can be a promising treatment option for such infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Humanos , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/fisiologia , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Quinolonas/farmacologia , Infecções Estafilocócicas/microbiologia , Fatores de Tempo
3.
Artigo em Inglês | MEDLINE | ID: mdl-30782985

RESUMO

Zidebactam and WCK 5153 are novel bicyclo-acyl hydrazide (BCH) agents that have previously been shown to act as ß-lactam enhancer (BLE) antibiotics in Pseudomonas aeruginosa and Acinetobacter baumannii The objectives of this work were to identify the molecular targets of these BCHs in Klebsiella pneumoniae and to investigate their potential BLE activity for cefepime and aztreonam against metallo-ß-lactamase (MBL)-producing strains in vitro and in vivo Penicillin binding protein (PBP) binding profiles were determined by Bocillin FL assay, and 50% inhibitory concentrations (IC50s) were determined using ImageQuant TL software. MICs and kill kinetics for zidebactam, WCK 5153, and cefepime or aztreonam, alone and in combination, were determined against clinical K. pneumoniae isolates producing MBLs VIM-1 or NDM-1 (plus ESBLs and class C ß-lactamases) to assess the in vitro enhancer effect of BCH compounds in conjunction with ß-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effects in vivo Zidebactam and WCK 5153 showed specific, high PBP2 affinity in K. pneumoniae The MICs of BLEs were >64 µg/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1 to >3 log10 kill against MBL-producing K. pneumoniae strains. Furthermore, the bactericidal synergy observed for these BLE-ß-lactam combinations translated well into in vivo efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of the ß-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors and display in vitro and in vivo BLE effects against multidrug-resistant (MDR) K. pneumoniae clinical isolates producing MBLs.

4.
J Med Chem ; 61(9): 4067-4086, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29627985

RESUMO

Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum ß-lactamases. The design of novel ß-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D ß-lactamases with unprecedented k2/ K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C ß-lactamses rapidly but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that 1-3 complexed with KPC-2 adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR Acinetobacter baumannii. Compounds 1-3 are novel ß-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted.

5.
Artigo em Inglês | MEDLINE | ID: mdl-28848013

RESUMO

Multidrug-resistant Acinetobacter baumannii has rapidly spread worldwide, resulting in a serious threat to hospitalized patients. Zidebactam and WCK 5153 are novel non-ß-lactam bicyclo-acyl hydrazide ß-lactam enhancer antibiotics being developed to target multidrug-resistant A. baumannii The objectives of this work were to determine the 50% inhibitory concentrations (IC50s) for penicillin-binding proteins (PBP), the OXA-23 inhibition profiles, and the antimicrobial activities of zidebactam and WCK 5153, alone and in combination with ß-lactams, against multidrug-resistant A. baumannii MICs and time-kill kinetics were determined for an A. baumannii clinical strain producing the carbapenemase OXA-23 and belonging to the widespread European clone II of sequence type 2 (ST2). Inhibition of the purified OXA-23 enzyme by zidebactam, WCK 5153, and comparators was assessed. All of the compounds tested displayed apparent Ki values of >100 µM, indicating poor OXA-23 ß-lactamase inhibition. The IC50s of zidebactam, WCK 5153, cefepime, ceftazidime, meropenem, and sulbactam (range of concentrations tested, 0.02 to 2 µg/ml) for PBP were also determined. Zidebactam and WCK 5153 demonstrated specific high-affinity binding to PBP2 of A. baumannii (0.01 µg/ml for both of the compounds). The MICs of zidebactam and WCK 5153 were >1,024 µg/ml for wild-type and multidrug-resistant Acinetobacter strains. Importantly, combinations of cefepime with 8 µg/ml of zidebactam or WCK 5153 and sulbactam with 8 µg/ml of zidebactam or WCK 5153 led to 4- and 8-fold reductions of the MICs, respectively, and showed enhanced killing. Notably, several of the combinations resulted in full bacterial eradication at 24 h. We conclude that zidebactam and WCK 5153 are PBP2 inhibitors that show a potent ß-lactam enhancer effect against A. baumannii, including a multidrug-resistant OXA-23-producing ST2 international clone.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Compostos Aza/farmacologia , Compostos Azabicíclicos/farmacologia , Ciclo-Octanos/farmacologia , Hidrazinas/farmacologia , Piperidinas/farmacologia , Acinetobacter baumannii/isolamento & purificação , Acinetobacter baumannii/metabolismo , Proteínas de Bactérias/metabolismo , Quimioterapia Combinada , Humanos , Concentração Inibidora 50 , Meropeném , Testes de Sensibilidade Microbiana , Proteínas de Ligação às Penicilinas/metabolismo , Sulbactam/farmacologia , Tienamicinas/farmacologia , Resistência beta-Lactâmica/efeitos dos fármacos , Resistência beta-Lactâmica/genética , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-28289035

RESUMO

Zidebactam and WCK 5153 are novel ß-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against Pseudomonas aeruginosa, including multidrug-resistant (MDR) metallo-ß-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal ß-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (mexR), porin-deficient (oprD), and AmpC-hyperproducing (dacB) derivatives of PAO1, and MBL-expressing clinical strains ST175 (blaVIM-2) and ST111 (blaVIM-1). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent Ki [Kiapp] > 100 µM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 µg/ml (amdinocillin MICs > 32 µg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 µg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested ß-lactams for each of the P. aeruginosa mutant strains. Likewise, antipseudomonal ß-lactams (CLSI breakpoints), in combination with 4 or 8 µg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. ß-Lactam-WCK enhancer combinations represent a promising ß-lactam "enhancer-based" approach to treat MDR P. aeruginosa infections, bypassing the need for MBL inhibition.


Assuntos
Compostos Azabicíclicos/farmacologia , Ciclo-Octanos/farmacologia , Piperidinas/farmacologia , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Proteínas de Ligação às Penicilinas/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia
9.
Bioorg Med Chem Lett ; 18(16): 4678-81, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18650090

RESUMO

In search for a new antibacterial agent with improved antimicrobial spectrum and potency, we designed and synthesized a series of novel 3-((Z)-2-(4-nitrophenyl)-2-(1H-tetrazol-5-yl) vinyl)-4H-chromen-4-ones 7a-h by convergent synthesis approach. All the synthesized compounds were assayed for their in-vitro antibacterial activities against gram-negative and gram-positive bacteria. The preliminary structure-activity relationship, to elucidate the essential structure requirements for the antimicrobial activity that results into anti-MRSA (methicillin-resistant S. aureus) potential, has been described. Amongst the synthesized compounds 7d, 7e, 7f and 7h were found to possess activity against methicillin-resistant S. aureus in addition to the activity against other bacterial strains such as E. faecalis, S. pneumoniae, and E. coli.


Assuntos
Antibacterianos/síntese química , Química Farmacêutica/métodos , Cromonas/síntese química , Resistência a Meticilina/efeitos dos fármacos , Tetrazóis/síntese química , Antibacterianos/farmacologia , Ácidos Carboxílicos/química , Cromonas/farmacologia , Desenho de Drogas , Escherichia coli/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Químicos , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia
10.
Antimicrob Agents Chemother ; 50(11): 3568-79, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16940059

RESUMO

WCK 771 is a broad-spectrum fluoroquinolone with enhanced activity against quinolone-resistant staphylococci. To understand the impact of the target-level interactions of WCK 771 on its antistaphylococcal pharmacodynamic properties, we determined the MICs for genetically defined mutants and studied the mutant prevention concentrations (MPCs), the frequency of mutation, and the cidality against the wild type and double mutants. There was a twofold increase in the MICs of WCK 771 for single gyrA mutants, indicating that DNA gyrase is its primary target. All first- and second-step mutants selected by WCK 771 revealed gyrA and grlA mutations, respectively. The MICs of WCK 771 and clinafloxacin were found to be superior to those of other quinolones against strains with double and triple mutations. WCK 771 was also cidal for high-density double mutants at low concentrations. WCK 771 and clinafloxacin showed narrow mutant selection windows compared to those of the other quinolones. Against a panel of 50 high-level quinolone-resistant clinical isolates of staphylococci (ciprofloxacin MIC > or = 16 microg/ml), the WCK 771 MPCs were < or =2 microg/ml for 68% of the strains and < or =4 microg/ml for 28% of the strains. Our results demonstrate that gyrA is the primary target of WCK 771 and that it has pharmacodynamic properties remarkably different from those of quinolones with dual targets (garenoxacin and moxifloxacin) and topoisomerase IV-specific quinolones (trovafloxacin). WCK 771 displayed an activity profile comparable to that of clinafloxacin, a dual-acting quinolone with a high affinity to DNA gyrase. Overall, the findings signify the key role of DNA gyrase in determining the optimal antistaphylococcal features of quinolones.


Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Quinolonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II , Farmacorresistência Bacteriana/genética , Inibidores Enzimáticos/farmacologia , Resistência a Meticilina/efeitos dos fármacos , Resistência a Meticilina/genética , Testes de Sensibilidade Microbiana , Mutação , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética
11.
Eur J Med Chem ; 40(12): 1325-30, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16126308

RESUMO

New series of 1-aryl-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic acid has been synthesized and the structures of the new compounds were established on the basis of 1H-NMR, mass (ES/MS), elemental analysis and IR spectral data. In vitro antibacterial activity (MIC activity) was evaluated and compared with standard drugs ciprofloxacin, sparfloxacin and trovafloxacin. Most of the compounds in the series have shown very interesting antibacterial activity against both gram-positive and gram-negative organisms. In this paper, we describe studies leading to identification of antibacterial agents incorporating novel pyridazine ring surrogate. In a gratifying result, the initial pyridazine-3-carboxylic acid analogues prepared were found to exhibit in vitro antibacterial activity approaching that of corresponding fluoroquinolone progenitor.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Antibacterianos/química , Ácidos Carboxílicos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridazinas/química , Relação Estrutura-Atividade
12.
Antimicrob Agents Chemother ; 48(12): 4754-61, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15561853

RESUMO

WCK 771, the arginine salt of S-(-)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC50) and the MIC90 of WCK 771 were 0.03 and 0.03 microg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 microg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 microg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains.


Assuntos
Antibacterianos/uso terapêutico , Fluoroquinolonas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Administração Oral , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Área Sob a Curva , Proteínas de Bactérias/genética , Celulite (Flegmão)/tratamento farmacológico , Celulite (Flegmão)/microbiologia , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/farmacologia , Meia-Vida , Injeções Subcutâneas , Resistência a Meticilina , Camundongos , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Quinolizinas/farmacocinética , Quinolizinas/farmacologia , Quinolizinas/uso terapêutico , Sepse/tratamento farmacológico , Sepse/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética
13.
Antimicrob Agents Chemother ; 48(9): 3338-42, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15328094

RESUMO

The activity of WCK 771, an experimental quinolone developed to overcome quinolone resistance in staphylococci and other bacteria, was determined against quinolone-susceptible and -resistant Staphylococcus aureus and S. epidermidis. WCK 771 MICs for 50 and 90% of the strains tested (MIC(50) and MIC(90), respectively) were 0.008 and 0.015 microg/ml for S. aureus (n = 43) and 0.015 and 0.03 microg/ml for S. epidermidis (n = 44) for quinolone-susceptible isolates, compared to ciprofloxacin values of 0.12 and 0.25 microg/ml and 0.25 and 0.5 microg/ml, respectively. Values for levofloxacin were 0.12 and 0.25 microg/ml and 0.12 and 0.25 microg/ml, those for clinafloxacin were 0.015 and 0.03 microg/ml and 0.015 and 0.03 microg/ml, those for moxifloxacin were 0.03 and 0.06 microg/ml and 0.06 and 0.12 microg/ml, and those for gatifloxacin were 0.06 and 0.12 microg/ml and 0.12 and 0.25 microg/ml, respectively. The WCK 771 MIC(50) and MIC(90), respectively, were 0.5 and 1 microg/ml for both species of staphylococci (n = 73 for S. aureus, n = 70 for S. epidermidis) for isolates highly resistant to ciprofloxacin (MIC(50) and MIC(90), >32 and >32 microg/ml, respectively). Values for levofloxacin were 8 and 32 microg/ml and 8 and 32 microg/ml, those for clinafloxacin were 1 and 2 microg/ml and 0.5 and 2 microg/ml, those for moxifloxacin 4 and >4 microg/ml and 4 and >4 microg/ml, and those for gatifloxacin were 4 and >4 microg/ml and 2 and >4 microg/ml, respectively. WCK 771 and clinafloxacin demonstrated MICs of 1 microg/ml against three vancomycin-intermediate strains. WCK 771 showed concentration-independent killing for up to 24 h at 2, 4, and 8 times the MICs against quinolone-resistant staphylococci and was also bactericidal after 8 h for high-density inocula (10(8) CFU/ml) of quinolone-resistant strains at 5 microg/ml, whereas moxifloxacin at 7.5 microg/ml was bacteriostatic. WCK 771 was not a substrate of the NorA efflux pump as evident from the similar MICs against both an efflux-positive and an efflux-negative strain. Overall, WCK 771 was the most potent quinolone tested against the staphylococci tested, regardless of quinolone susceptibility.


Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Staphylococcus/efeitos dos fármacos , Proteínas de Bactérias/genética , Contagem de Colônia Microbiana , Farmacorresistência Bacteriana , Humanos , Cinética , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Quinolonas/farmacologia , Infecções Estafilocócicas/microbiologia
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