Cellular pharmacokinetics and intracellular activity of the bacterial fatty acid synthesis inhibitor, afabicin desphosphono against different resistance phenotypes of Staphylococcus aureus in models of cultured phagocytic cells

Abstract

Cellular pharmacokinetics and intracellular activity of the bacterial fatty acid synthesis inhibitor afabicin desphosphono against different resistance phenotypes of

The Persister Character of Clinical Isolates of Staphylococcus aureus Contributes to Faster Evolution to Resistance and Higher Survival in THP-1 Monocytes: A Study With Moxifloxacin

“…The activity of moxifloxacin against intracellular bacteria was measured using full concentrationresponse experiments (change in intracellular CFU from the post-phagocytosis inoculum plotted against the extracellular antibiotic concentration [both in log 10 units] typically ranging from 10 −2 to 10 +2 fold the MIC). A Hill-Langmuir equation [with slope factor set to 1 as discussed previously (Lemaire et al, 2009;Peyrusson et al, 2019)] was fitted to the data to calculate two key pharmacodynamic parameters [apparent static concentration (C s ) and maximal relative efficacy (E max ); see Buyck et al (2016) and in the caption of Figure 4].…”

“…Focusing on intracellular infection, the presence of persisters within the host cells may be a key determinant in the intracellular survival of small but significant inocula for many bacteria (Fisher et al, 2017). We and others have further documented that antibiotics are unable to eradicate intracellular Staphylococcus aureus even upon exposure of the host cells to high concentrations (typically 100-fold their MIC) of highly bactericidal agents (Krut et al, 2004;Barcia-Macay et al, 2006;Lemaire et al, 2011;Peyrusson et al, 2019), leaving apparently untouched about 0.1-1% of the original inoculum (Peyrusson et al, 2019). This contrasts with the observed extracellular activity of these drugs, which are capable of bringing CFU counts below the limit of detection in a very short time and often at concentrations that are only a few multiples of their MIC.…”

Bacterial antimicrobial resistance and dermatological ramifications*

“…70 Promising new antibiotic strategies include inhibition of novel targets in bacterial metabolic and survival pathways and hybrid agents that are mechanistically more effective and hardier to resistance than their individual components (Table S2; see Supporting Information). [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100] Beyond conventional drug development, innovative applications of nanoparticles (NPs), phage therapy, endolysins, antimicrobial peptides (AMPs), CRISPR, biofilm and microbiome modulators have the potential to revolutionize antimicrobial therapy. 71 NPs exert their antimicrobial activity by disrupting cell membranes and intracellular contents.…”