Monensin — a perturbant of cellular physiology

Ledger, Philip W.; Tanzer, Marvin L.

doi:10.1016/0968-0004(84)90299-8

Cited by 96 publications

(45 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Over the same range of pH, the accumulation of moxifloxacin was decreased 2-to 3-fold. To investigate the potential role of pH gradients between the extracellular and intracellular milieus, we then measured the accumulation of fluoroquinolones in the presence of NH 4 Cl (to neutralize the lysosomal pH) and of monensin (to collapse the pH gradient between the extracellular and intracellular compartments (23,28). Opposite effects were observed for the two fluoroquinolones under these two conditions.…”

Section: Resultsmentioning

confidence: 99%

Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin againstStaphylococcus aureus

Lemaire

Tulkens

Bambeke

2011

Antimicrob Agents Chemother

167

140

View full text Add to dashboard Cite

In contrast to currently marketed fluoroquinolones, which are zwitterionic, delafloxacin is an investigational fluoroquinolone with an anionic character that is highly active against Gram-positive bacteria. We have examined the effect of acidic pH on its accumulation in Staphylococcus aureus and in human THP-1 cells, in parallel with its activity against extracellular and intracellular S. aureus. Moxifloxacin was used as a comparator. Delafloxacin showed MICs 3 to 5 log 2 dilutions lower than those of moxifloxacin for a collection of 35 strains with relevant resistance mechanisms and also proved to be 10-fold more potent against intracellular S. aureus ATCC 25923. In medium at pH 5.5, this difference was further enhanced, with the MIC decreasing by 5 log 2 dilutions. In infected cells incubated in acidic medium, the relative potency was 10-fold higher than that at neutral pH and the maximal relative efficacy reached a bactericidal effect at 24 h. These results can be explained by a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH, making delafloxacin one of the most efficient drugs tested in this model. Opposite effects were seen for moxifloxacin with respect to both activity and accumulation. As reported for zwitterionic fluoroquinolones, delafloxacin was found associated with the soluble fraction in homogenates of eukaryotic cells. Taken together, these properties may confer to delafloxacin an advantage for the eradication of S. aureus in acidic environments, including intracellular infections.Fluoroquinolones are one of the first families of fully synthetic antibiotics with large clinical use, and they represent a wide range of molecules, which permits the establishment of in-depth structure-activity relationships (16,17). Over the last 20 years, most fluoroquinolone research efforts have been focused on new molecules with improved activity toward Grampositive cocci because of the increasing spread of multiresistant staphylococci and streptococci. The 8-methoxy fluoroquinolone moxifloxacin is the first example of this new generation to reach the commercial market. It combines many desirable microbiological and pharmacokinetic properties (rapid bactericidal activity, a spectrum covering pertinent pathogens, excellent oral bioavailability, a large tissue distribution, and a propensity to accumulate within eukaryotic cells [see reference 45 for a review]). Moxifloxacin shows extensive activity toward bacteria thriving in the cytosol (Listeria monocytogenes [14]), phagosomes (Legionella pneumophila, Mycobacterium avium, and Mycobacterium tuberculosis [5,9,46]), and phagolysosomes (Staphylococcus aureus [6]), suggesting that it easily diffuses between different subcellular compartments. Yet moxifloxacin activity is partially defeated by the acidic pH prevailing in vacuolar subcellular compartments (6).Delafloxacin [RX-3341; 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] is an investigational fluoro...

show abstract

Section: Resultsmentioning

confidence: 99%

Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin againstStaphylococcus aureus

Lemaire

Tulkens

Bambeke

2011

Antimicrob Agents Chemother

167

140

View full text Add to dashboard Cite

show abstract

“…Since HCO3-transport at pH 8.0 required millimolar Na+ concentrations in the extracellular medium, while CO2 transport is stimulated by much lower concentrations (5, 11), we postulated that an actual Na+ gradient across the plasmalemma might be more involved in HCO3-rather than in CO2 transport. The ionophore monensin catalyzes the elctroneutral exchange of Na+ and H+ across biological membranes (9) and thus collapses Na+ gradients. In this experiment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chlorophyll a Fluorescence Yield as a Monitor of Both Active CO₂ and HCO₃⁻ Transport by the Cyanobacterium Synechococcus UTEX 625

Miller¹,

Espie²,

Canvin³

1988

Plant Physiol.

View full text Add to dashboard Cite

Simultaneous measurements have been made of inorganic carbon accumulation (by mass spectrometry) and chlorophyll a fluorescence yield of the cyanobacterium Synechococcus UTEX 625. The accumulation of inorganic carbon by the cells was accompanied by a substantial quenching of chlorophyll a fluorescence. The quenching occurred even when CO2 fixation was inhibited by iodoacetamide and whether the accumulation of inorganic carbon resulted from either active CO2 or HCO3-transport. Measurement of chlorophyll a fluorescence yield of cyanobacteria may prove to be a rapid and convenient means of screening for mutants of inorganic carbon accumulation.We have shown that the cyanobacterium Synechococcus UTEX 625 can actively transport both CO2 and HCO3- (5,6,10,11,21). Other cyanobacteria, both unicellular and filamentous, have similar abilities (1,2,6,8,13,14,16,17, 22). The active transport of CO2 can be unambiguously monitored by mass spectrometry (2, 3). Unfortunately, HCO3-transport can be monitored by mass spectrometry only in the presence of carbonic anhydrase (2, 3), which is known to stimulate CO2 transport (10). The transport and accumulation of DIC2 can be monitored under some circumstances by the centrifugal filtration of cells through a layer of silicone fluid after they have been incubated in 14C-DIC (8, 13). This is a very useful method, especially for the study of HCO3-transport. It does, however, have a number of drawbacks. It is a rather laborious technique, not well suited to screening a large number of samples, as is necessary in a search for DIC transport mutants. Also, the cells cannot be separated fast enough from the incubation solution to allow proper monitoring of CO2 transport in many cases (AG Miller, GS Espie, DT Canvin, unpublished data). DIC transport can be monitored by IR gas analysis (16,18), but the method is restricted to the study of cell suspensions at pH 7.5 or below.We

show abstract

“…Treatment of infected cells with tunicamycin gave a similar result to that obtained with N-glycanase treatment, confirming the presence of N-linked carbohydrate, but treatment with monensin resulted in a total lack of reaction with MAb P68. Monensin has a wide range of effects on the cell (Ledger & Tanzer, 1984), and so the lack of immunological reactivity may be due to factors other than glycosylation.…”

Section: Discussionmentioning

confidence: 99%

Glycoprotein 60 of equine herpesvirus type 1 is a homologue of herpes simplex virus glycoprotein D and plays a major role in penetration of cells

Whittaker

Taylor

Elton

et al. 1992

Journal of General Virology

View full text Add to dashboard Cite

Monoclonal antibodies (MAbs) specific for equine herpesvirus type 1 (EHV-1) glycoprotein 60 (gp60) and gp17/18 (F3132 and 5H6 respectively) were found to react with the same protein, which was identified as a homologue of herpes simplex virus type 1 gD. MAb F3132 strongly neutralized virus infectivity and inhibited the penetration of the virus into the cell. The effects on penetration were shared with three other MAbs against this protein (P68, F3116 and F3129), but no effect on virus penetration was found with any other anti-EHV-1 MAb tested. The level ofglycosylation ofgp60 was analysed using glycanase enzymes and glycosylation inhibitors, and consisted of mainly Nlinked carbohydrate. The Mr of non-N-glycosylated gp60 was 50K.

show abstract

Monensin — a perturbant of cellular physiology

Cited by 96 publications

References 15 publications

Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin againstStaphylococcus aureus

Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin againstStaphylococcus aureus

Chlorophyll a Fluorescence Yield as a Monitor of Both Active CO₂ and HCO₃⁻ Transport by the Cyanobacterium Synechococcus UTEX 625

Glycoprotein 60 of equine herpesvirus type 1 is a homologue of herpes simplex virus glycoprotein D and plays a major role in penetration of cells

Contact Info

Product

Resources

About

Monensin — a perturbant of cellular physiology

Cited by 96 publications

References 15 publications

Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin againstStaphylococcus aureus

Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin againstStaphylococcus aureus

Chlorophyll a Fluorescence Yield as a Monitor of Both Active CO2 and HCO3− Transport by the Cyanobacterium Synechococcus UTEX 625

Glycoprotein 60 of equine herpesvirus type 1 is a homologue of herpes simplex virus glycoprotein D and plays a major role in penetration of cells

Contact Info

Product

Resources

About

Chlorophyll a Fluorescence Yield as a Monitor of Both Active CO₂ and HCO₃⁻ Transport by the Cyanobacterium Synechococcus UTEX 625