First Evidence of a Combination of Terpinen-4-ol and α-Terpineol as a Promising Tool against ESKAPE Pathogens.

Antimicrobial resistance is a major public health issue raising growing concern in the face of dwindling response options. It is therefore urgent to find new anti-infective molecules enabling us to fight effectively against ever more numerous bacterial infections caused by ever more antibiotic-resistant bacteria. In this quest for new antibacterials, essential oils (or compounds extracted from essential oils) appear to be a promising therapeutic option. In the present work, we investigate the potential antibacterial synergy between a combination of terpinen-4-ol and α-terpineol (10:1) compared to standard tea tree oil. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined. Then, time kill assays, in vitro cytotoxicity and bactericidal activity on latent bacteria (persisters) were investigated. Finally, an in silico study of the pharmacokinetic parameters of α-terpineol was also performed. Altogether, our data demonstrate that the combination of terpinen-4-ol and α-terpineol might be a precious weapon to address ESKAPE pathogens.

Antimicrobial Spectrum of Titroleane™: A New Potent Anti-Infective Agent.

Tea Tree oil (TTO) is well known for its numerous good properties but might be also irritating or toxic when used topically or ingested, thus limiting the number of possible applications in Humans. The aim of the study was to characterize the antimicrobial spectrum as well as the toxicity of Titroleane™, a new anti-infective agent obtained from TTO but cleared of its toxic monoterpenes part. The susceptibility to Titroleane™ of various pathogens (bacteria and fungi) encountered in animal and human health was studied in comparison with that of TTO. Antimicrobial screening was carried out using the broth microdilution method. Activities against aerobic, anaerobic, fastidious and non-fastidious microorganisms were performed. For all microorganisms tested, the MIC values for Titroleane™ ranged from 0.08% to 2.5%, except for Campylobacter jejuni, and Aspergillus niger. In particular, Titroleane™ showed good efficacy against skin and soft tissue infection pathogens, such as methicillin resistant Staphylococcus aureus (MRSA), intra-abdominal infections and oral pathogens, as well as fish farming pathogens. Toxicity testing showed little and similar cytotoxicities between TTO and Titroleane™ of 37% and 23%, respectively at a concentration of 0.025% (v/v). Finally, we demonstrated that the antimicrobial activity of Titroleane™ is similar to that of TTO.

The replication kinase Cdc7-Dbf4 promotes the interaction of the p150 subunit of chromatin assembly factor 1 with proliferating cell nuclear antigen.

The coordination of chromatin assembly with DNA replication, which is essential for genomic stability, requires the combined activation of histone deposition with the firing of replication origins. We report here the direct interaction of chromatin assembly factor 1 (CAF1), a key factor involved in histone deposition, with the replication kinase Cdc7-Dbf4. We isolated a complex containing both the largest subunit of CAF1 (p150) and the Cdc7-Dbf4 kinase specifically in S phase and thus prove the existence of this interaction in vivo. We then show that the Cdc7-Dbf4 kinase efficiently phosphorylates p150. This event induces a change in p150 oligomerization state, which promotes binding to proliferating cell nuclear antigen (PCNA). Conversely, CAF1 recruitment is reduced in a PCNA/DNA loading assay using Cdc7-depleted extracts. Our data define p150 as a new target for this kinase with implications for the coordination between DNA replication and CAF1 functions.