Facilitated Permeation of Antibiotics across Membrane Channels − Interaction of the Quinolone Moxifloxacin with the OmpF Channel

Mach, Tivadar; Neves, Patrícia; Spiga, Enrico; Weingart, Helge; Winterhalter, Mathias; Ruggerone, Paolo; Ceccarelli, Matteo; Gameiro, Paula

doi:10.1021/ja803188c

Cited by 59 publications

(79 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is noteworthy that the two different sets of reaction coordinates used in this manuscript reproduce well the previously obtained experimental observations [10,11]. Indeed, both resulting simulations reveal the same "macroscopic event" that is the passage/diffusion of the antibiotic and both find a preferential affinity site for the antibiotic inside the channel.…”

Section: Discussionsupporting

confidence: 78%

See 1 more Smart Citation

Investigating reaction pathways in rare events simulations of antibiotics diffusion through protein channels

et al. 2010

Self Cite

View full text Add to dashboard Cite

In Gram-negative bacteria, outer-membrane protein channels, such as OmpF of Escherichia coli, constitute the entry point of various classes of antibiotics. While antibacterial research and development is declining, bacterial resistance to antibiotics is rising and there is an emergency call for a new way to develop potent antibacterial agents and to bring them to the market faster and at reduced cost. An emerging strategy is to follow a bottom-up approach based on microscopically founded computational based screening, however such strategy needs better-tuned methods. Here we propose to use molecular dynamics (MD) simulations combined with the metadynamics algorithm, to study antibiotic translocation through OmpF at a molecular scale. This recently designed algorithm overcomes the time scale problem of classical MD by accelerating some reaction coordinates. It is expected that the initial assumption of the reaction coordinates is a key determinant for the efficiency and accuracy of the simulations. Previous studies using different computational schemes for a similar process only used one reaction coordinate, which is the directionality. Here we go further and see how it is possible to include more informative reaction coordinates, accounting explicitly for: (i) the antibiotic flexibility and (ii) interactions with the channel. As model systems, we select two compounds covering the main classes of antibiotics, ampicillin and moxifloxacine. We decipher the molecular mechanism of translocation of each antibiotic and highlight the important parameters that should be taken into account for improving further simulations. This will benefit the screening and design for antibiotics with better permeation properties

show abstract

Section: Discussionsupporting

confidence: 78%

“…Our approach will allow discussing the two choices of RC in the translocation with the study of two different antibiotics: the beta-lactam ampicillin and the quinolone moxifloxacine, for which experimental data and simulations are already available [10,11].…”

Section: Introductionmentioning

confidence: 99%

Investigating reaction pathways in rare events simulations of antibiotics diffusion through protein channels

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…The complex cell membrane of Pseudomonas aeruginosa is an effective barrier for preventing cellular activity of these new TMK inhibitors because growth inhibition did not occur even in an efflux pump knockout strain. It has been proposed that quinolones penetrate the outer membrane of Gram negative bacteria by translocation through the OmpF channel (in case of P. aeruginosa , OprD 40 ) due to their unique zwitterionic nature 41 ; the inner membrane is crossed and the cytosol accessed due to the substantial amount of uncharged properties in the zwitterions. 42 Therefore, incorporating zwitterions into the inhibitors is a plausible next strategy for penetrating the complex cell membrane of Gram negative bacteria and to inhibit P. aeruginosa bacteria cell growth and division.…”

Section: Resultsmentioning

confidence: 99%

Structure Guided Development of Novel Thymidine Mimetics Targeting Pseudomonas aeruginosa Thymidylate Kinase: From Hit to Lead Generation

Choi

Plummer²,

Starr³

et al. 2012

J. Med. Chem.

View full text Add to dashboard Cite

Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogs, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC50 = 58 μM), which has reasonable inhibition potency against Pseudomonas aeruginosa TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP5A in a PaTMK homology model. This hit (1) was co-crystallized with PaTMK, and several potent PaTMK inhibitors (leads, 46, 47, 48, and 56, IC50 = 100–200 nM) were synthesized using computer aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs, but not with human TMK which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray co-crystal structures, homology models, and SAR results.

show abstract

“…As per these observations (10,11), an uncharged complex would be better absorbed through various biological membranes and would show higher bioavailability than the charged one. This would lead to enhanced levels of both the fluoroquinolone antibacterials and bismuth ions at the site of action.…”

mentioning

confidence: 79%

“…Transport of quinolones across the bacterial cytoplasmic membrane is strongly pH dependent, peaking at neutral pH. It has been proposed that uncharged quinolone species are responsible for diffusion through cytoplasmic membranes (10) and the presence of metal ions results in higher uptake of quinolones by bacterial cells when compared to the drug alone (11). Therefore, the formation of metal complexes is likely to increase the bioavailability of metal ions or ligands or both.…”

mentioning

confidence: 99%

Metalloantibiotics: Synthesis, characterization and antimicrobial evaluation of bismuth-fluoroquinolone complexes against Helicobacter pylori

Shaikh¹,

Giridhar²,

Mégraud³

et al. 2009

Acta Pharmaceutica

View full text Add to dashboard Cite

Helicobacter pylori, a Gram-negative microaerophilic bacterium, a prevalent human pathogen in the gastric mucosa, is responsible for gastric and duodenal ulcers (1). In H. pylori infections the therapeutic aim is complete eradication of H. pylori in the stomach. The current therapy of choice is a triple combination that consists of an acid inhibitor, for example a proton pump inhibitor such as omeprazole, and two antibiotics, such as clarithromycin and amoxicillin. This triple therapy is, however, associated with disadvantages (2). As a result of differing diffusion properties, the three different substances, which should act together, do not reach uniformly the inflammatory foci caused by H. pylori. Thus, in order to achieve good healing results, very high doses, which are accompanied by serious side effects, are necessary. It is obvious that a triple therapy has also other great disadvantages in comparison with administration of only one medicament or even of two medicaments (3). Novel organometallic compounds have been prepared by complexing the fluoroquinolones, norfloxacin, ofloxacin, ciprofloxacin, sparfloxacin, lomefloxacin, pefloxacin and gatifloxacin, with bismuth. The complexes were characterized by UV, IR, atomic absorption spectroscopy, elemental analysis, differential scanning calorimetry, thermogravimetric analysis and mass spectrometry. Their antibacterial potential against Helicobacter pylori and other microorganisms was investigated. These compounds were found to possess strong activity against Helicobacter pylori with a minimum inhibitory concentration of 0.5 mg L -l . They also exhibited moderate activity against Escherichia coli, Staphylococcus aureus, Bacillus pumilus and Staphylococcus epidermidis. These bismuth-fluoroquinolone complexes have the potential to be developed as drugs against H. pylori related ailments.

show abstract

Facilitated Permeation of Antibiotics across Membrane Channels − Interaction of the Quinolone Moxifloxacin with the OmpF Channel

Cited by 59 publications

References 72 publications

Investigating reaction pathways in rare events simulations of antibiotics diffusion through protein channels

Investigating reaction pathways in rare events simulations of antibiotics diffusion through protein channels

Structure Guided Development of Novel Thymidine Mimetics Targeting Pseudomonas aeruginosa Thymidylate Kinase: From Hit to Lead Generation

Metalloantibiotics: Synthesis, characterization and antimicrobial evaluation of bismuth-fluoroquinolone complexes against Helicobacter pylori

Contact Info

Product

Resources

About