F. Bambeke | UCLouvain (University of Louvain) (original) (raw)

Papers by F. Bambeke

Antimicrobial Agents and Chemotherapy, 2012

In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we ... more In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we evaluated the intracellular fate of menD and hemB mutants (corresponding to menadione-and hemin-dependent small-colony variants, respectively) of the parental COL methicillin-resistant Staphylococcus aureus strain and the pharmacodynamic profile of the intracellular activity of a series of antibiotics in human THP-1 monocytes. We have now examined the phagocytosis and intracellular persistence of the same strains in THP-1 cells activated by phorbol 12-myristate 13-acetate (PMA) and measured the intracellular activity of gentamicin, moxifloxacin, and oritavancin in these cells. Postphagocytosis intracellular counts and intracellular survival were lower in PMA-activated cells, probably due to their higher killing capacities. Gentamicin and moxifloxacin showed a 5-to 7-fold higher potency (lower static concentrations) against the parental strain, its hemB mutant, and the genetically complemented strain in . In parallel, we observed that the MICs of these drugs were markedly reduced if bacteria had been preexposed to H 2 O 2 . In contrast, the intracellular potency of oritavancin was not different in activated and nonactivated cells and was not decreased by the addition of N-acetylcysteine, regardless of the phenotype of the strains. The oritavancin MIC was also unaffected by preincubation of the bacteria with H 2 O 2 . Thus, activation of THP-1 cells by PMA may increase the intracellular potency of certain antibiotics (probably due to synergy with reactive oxygen species), but this effect cannot be generalized to all antibiotics.

Archiv der Pharmazie, 2009

The enhancement of bacterial resistance of pathogens to currently available antibiotics constitut... more The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compounds with a potent antimicrobial profile, we designed and synthesized low molecular weight 2-mercaptobenzothiazole derivatives 2a -2l and 3a -3l. Both series were screened for in-vitro antibacterial activity against the representative panel of Gram-positive and Gram-negative bacteria strains. The biological screening identified compounds 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 lg/mL against Staphylococcus aureus and 25 lg/mL against Escherichia coli, respectively. The replacement of the S-H by the S-Bn moiety resulted in considerable loss of the antibacterial action of the 3a -3l series. The antibiotic action of compounds 2e and 2l was also investigated by testing their activity against some clinical isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our molecules was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compounds by MTS assay against HeLa and MRC-5 cell lines. Reagents and conditions: a) DMF, 1608C, 1 h; b) K2CO3, H2O/dioxane, 758C, 15 min; c) Ar-CH2-Br, Bu4NBr3, p-anisidine, CH2Cl2/CH3OH, r.t., 2 h. Scheme 1. Synthetic routes of compounds 1d, 2a -2f, and 3a -3l.

Journal of Antimicrobial Chemotherapy, 2012

Objectives: The aim of this study was to investigate different hydrophobic gentamicin formulation... more Objectives: The aim of this study was to investigate different hydrophobic gentamicin formulations [gentamicin-bis(2-ethylhexyl) sulfosuccinate (GEN-AOT), microstructured GEN-AOT (PCA GEN-AOT) and GEN-AOT-loaded poly(lactide-co-glycolide) acid (PLGA) nanoparticles (NPs)] in view of improving its therapeutic index against intracellular bacteria. The intracellular accumulation, subcellular distribution and intracellular activity of GEN-AOT and NPs in different monocytic -macrophagic cell lines were studied.

Antimicrobial Agents and Chemotherapy, 2013

The pharmacodynamic properties governing the activities of antibiotics against intracellular Stap... more The pharmacodynamic properties governing the activities of antibiotics against intracellular Staphylococcus aureus are still largely undetermined. Sixteen antibiotics of seven different pharmacological classes (azithromycin and telithromycin [macrolides]; gentamicin [an aminoglycoside]; linezolid [an oxazolidinone]; penicillin V, nafcillin, ampicillin, and oxacillin [␤-lactams]; teicoplanin, vancomycin, and oritavancin [glycopeptides]; rifampin [an ansamycin]; and ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin [quinolones]) have been examined for their activities against S.

Antimicrobial Agents and Chemotherapy, 2012

In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we ... more In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we evaluated the intracellular fate of menD and hemB mutants (corresponding to menadione-and hemin-dependent small-colony variants, respectively) of the parental COL methicillin-resistant Staphylococcus aureus strain and the pharmacodynamic profile of the intracellular activity of a series of antibiotics in human THP-1 monocytes. We have now examined the phagocytosis and intracellular persistence of the same strains in THP-1 cells activated by phorbol 12-myristate 13-acetate (PMA) and measured the intracellular activity of gentamicin, moxifloxacin, and oritavancin in these cells. Postphagocytosis intracellular counts and intracellular survival were lower in PMA-activated cells, probably due to their higher killing capacities. Gentamicin and moxifloxacin showed a 5-to 7-fold higher potency (lower static concentrations) against the parental strain, its hemB mutant, and the genetically complemented strain in . In parallel, we observed that the MICs of these drugs were markedly reduced if bacteria had been preexposed to H 2 O 2 . In contrast, the intracellular potency of oritavancin was not different in activated and nonactivated cells and was not decreased by the addition of N-acetylcysteine, regardless of the phenotype of the strains. The oritavancin MIC was also unaffected by preincubation of the bacteria with H 2 O 2 . Thus, activation of THP-1 cells by PMA may increase the intracellular potency of certain antibiotics (probably due to synergy with reactive oxygen species), but this effect cannot be generalized to all antibiotics.

Antimicrobial Agents and Chemotherapy, 2011

The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been associated with diffic... more The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been associated with difficult-totreat infections, reduced antimicrobial susceptibility, and intracellular persistence. This study represents a detailed intra-and extracellular investigation of a clinical wild-type (WT) S. aureus strain and its counterpart with an SCV phenotype both in vitro and in vivo, using the THP-1 cell line model and the mouse peritonitis model, respectively. Bacteria of both phenotypes infected the mouse peritoneum intra-and extracellularly. The SCV phenotype was less virulent and showed distinct bacterial clearance, a reduced multiplication capacity, and a reduced internalization ability. However, some of the SCV-infected mice were still culture positive up to 96 h postinfection, and bacteria of this phenotype could spread to the mouse kidney and furthermore revert to the more virulent WT phenotype in both the mouse peritoneum and kidney. The SCV phenotype is therefore, despite reduced virulence, an important player in S. aureus pathogenesis. In the THP-1 cell line model, both dicloxacillin (DCX) and linezolid (LZD) reduced the intracellular inocula of bacteria of both phenotypes by approximately 1 to 1.5 log 10 in vitro, while DCX was considerably more effective against extracellular bacteria. In the mouse peritonitis model, DCX and LZD were also able to control both intra-and extracellular infections caused by either phenotype. Treatment with a single dose of DCX and LZD was, however, insufficient to clear the SCVs in the kidneys, and the risk of recurrent infection remained. This stresses the importance of an optimal dosing of the antibiotic when SCVs are present.

Antimicrobial Agents and Chemotherapy, 2012

In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we ... more In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we evaluated the intracellular fate of menD and hemB mutants (corresponding to menadione-and hemin-dependent small-colony variants, respectively) of the parental COL methicillin-resistant Staphylococcus aureus strain and the pharmacodynamic profile of the intracellular activity of a series of antibiotics in human THP-1 monocytes. We have now examined the phagocytosis and intracellular persistence of the same strains in THP-1 cells activated by phorbol 12-myristate 13-acetate (PMA) and measured the intracellular activity of gentamicin, moxifloxacin, and oritavancin in these cells. Postphagocytosis intracellular counts and intracellular survival were lower in PMA-activated cells, probably due to their higher killing capacities. Gentamicin and moxifloxacin showed a 5-to 7-fold higher potency (lower static concentrations) against the parental strain, its hemB mutant, and the genetically complemented strain in . In parallel, we observed that the MICs of these drugs were markedly reduced if bacteria had been preexposed to H 2 O 2 . In contrast, the intracellular potency of oritavancin was not different in activated and nonactivated cells and was not decreased by the addition of N-acetylcysteine, regardless of the phenotype of the strains. The oritavancin MIC was also unaffected by preincubation of the bacteria with H 2 O 2 . Thus, activation of THP-1 cells by PMA may increase the intracellular potency of certain antibiotics (probably due to synergy with reactive oxygen species), but this effect cannot be generalized to all antibiotics.

Archiv der Pharmazie, 2009

The enhancement of bacterial resistance of pathogens to currently available antibiotics constitut... more The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compounds with a potent antimicrobial profile, we designed and synthesized low molecular weight 2-mercaptobenzothiazole derivatives 2a -2l and 3a -3l. Both series were screened for in-vitro antibacterial activity against the representative panel of Gram-positive and Gram-negative bacteria strains. The biological screening identified compounds 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 lg/mL against Staphylococcus aureus and 25 lg/mL against Escherichia coli, respectively. The replacement of the S-H by the S-Bn moiety resulted in considerable loss of the antibacterial action of the 3a -3l series. The antibiotic action of compounds 2e and 2l was also investigated by testing their activity against some clinical isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our molecules was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compounds by MTS assay against HeLa and MRC-5 cell lines. Reagents and conditions: a) DMF, 1608C, 1 h; b) K2CO3, H2O/dioxane, 758C, 15 min; c) Ar-CH2-Br, Bu4NBr3, p-anisidine, CH2Cl2/CH3OH, r.t., 2 h. Scheme 1. Synthetic routes of compounds 1d, 2a -2f, and 3a -3l.

Journal of Antimicrobial Chemotherapy, 2012

Objectives: The aim of this study was to investigate different hydrophobic gentamicin formulation... more Objectives: The aim of this study was to investigate different hydrophobic gentamicin formulations [gentamicin-bis(2-ethylhexyl) sulfosuccinate (GEN-AOT), microstructured GEN-AOT (PCA GEN-AOT) and GEN-AOT-loaded poly(lactide-co-glycolide) acid (PLGA) nanoparticles (NPs)] in view of improving its therapeutic index against intracellular bacteria. The intracellular accumulation, subcellular distribution and intracellular activity of GEN-AOT and NPs in different monocytic -macrophagic cell lines were studied.

Antimicrobial Agents and Chemotherapy, 2013

The pharmacodynamic properties governing the activities of antibiotics against intracellular Stap... more The pharmacodynamic properties governing the activities of antibiotics against intracellular Staphylococcus aureus are still largely undetermined. Sixteen antibiotics of seven different pharmacological classes (azithromycin and telithromycin [macrolides]; gentamicin [an aminoglycoside]; linezolid [an oxazolidinone]; penicillin V, nafcillin, ampicillin, and oxacillin [␤-lactams]; teicoplanin, vancomycin, and oritavancin [glycopeptides]; rifampin [an ansamycin]; and ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin [quinolones]) have been examined for their activities against S.

Antimicrobial Agents and Chemotherapy, 2012

In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we ... more In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700 -3711, 2012), we evaluated the intracellular fate of menD and hemB mutants (corresponding to menadione-and hemin-dependent small-colony variants, respectively) of the parental COL methicillin-resistant Staphylococcus aureus strain and the pharmacodynamic profile of the intracellular activity of a series of antibiotics in human THP-1 monocytes. We have now examined the phagocytosis and intracellular persistence of the same strains in THP-1 cells activated by phorbol 12-myristate 13-acetate (PMA) and measured the intracellular activity of gentamicin, moxifloxacin, and oritavancin in these cells. Postphagocytosis intracellular counts and intracellular survival were lower in PMA-activated cells, probably due to their higher killing capacities. Gentamicin and moxifloxacin showed a 5-to 7-fold higher potency (lower static concentrations) against the parental strain, its hemB mutant, and the genetically complemented strain in . In parallel, we observed that the MICs of these drugs were markedly reduced if bacteria had been preexposed to H 2 O 2 . In contrast, the intracellular potency of oritavancin was not different in activated and nonactivated cells and was not decreased by the addition of N-acetylcysteine, regardless of the phenotype of the strains. The oritavancin MIC was also unaffected by preincubation of the bacteria with H 2 O 2 . Thus, activation of THP-1 cells by PMA may increase the intracellular potency of certain antibiotics (probably due to synergy with reactive oxygen species), but this effect cannot be generalized to all antibiotics.

Antimicrobial Agents and Chemotherapy, 2011

The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been associated with diffic... more The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been associated with difficult-totreat infections, reduced antimicrobial susceptibility, and intracellular persistence. This study represents a detailed intra-and extracellular investigation of a clinical wild-type (WT) S. aureus strain and its counterpart with an SCV phenotype both in vitro and in vivo, using the THP-1 cell line model and the mouse peritonitis model, respectively. Bacteria of both phenotypes infected the mouse peritoneum intra-and extracellularly. The SCV phenotype was less virulent and showed distinct bacterial clearance, a reduced multiplication capacity, and a reduced internalization ability. However, some of the SCV-infected mice were still culture positive up to 96 h postinfection, and bacteria of this phenotype could spread to the mouse kidney and furthermore revert to the more virulent WT phenotype in both the mouse peritoneum and kidney. The SCV phenotype is therefore, despite reduced virulence, an important player in S. aureus pathogenesis. In the THP-1 cell line model, both dicloxacillin (DCX) and linezolid (LZD) reduced the intracellular inocula of bacteria of both phenotypes by approximately 1 to 1.5 log 10 in vitro, while DCX was considerably more effective against extracellular bacteria. In the mouse peritonitis model, DCX and LZD were also able to control both intra-and extracellular infections caused by either phenotype. Treatment with a single dose of DCX and LZD was, however, insufficient to clear the SCVs in the kidneys, and the risk of recurrent infection remained. This stresses the importance of an optimal dosing of the antibiotic when SCVs are present.