Abstract
The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment solutions. It has been shown in vitro that phenothiazines can act as adjuvants to antibiotics whereby the minimum inhibitory concentration (MIC) of the antibiotic is decreased. However, phenothiazines do not perform well in vivo, most likely because they can permeate the blood-brain (BBB) barrier and cause severe side-effects to the central nervous system. Therefore, the aim of this study was to synthesize a promazine derivate that would not cross the BBB but retain its properties as antimicrobial helper compound. Surprisingly, in vitro studies showed that the novel compound, JBC 1847 exhibited highly increased antimicrobial activity against eight Gram-positive pathogens (MIC, 0.5–2 mg/L), whereas a disc diffusion assay indicated that the properties as an adjuvant were lost. JBC 1847 showed significant (P < 0.0001) activity against a Staphylococcus aureus strain compared with the vehicle, in an in vivo wound infection model. However, both in vitro and in silico analyses showed that JBC 1847 possesses strong affinity for human plasma proteins and an Ames test showed that generally, it is a non-mutagenic compound. Finally, in silico predictions suggested that the compound was not prone to pass the BBB and had a suitable permeability to the skin. In conclusion, JBC 1847 is therefore suggested to hold potential as a novel topical agent for the clinical treatment of S. aureus skin and soft tissue infections, but pharmacokinetics and pharmacodynamics need to be further investigated.
Highlights
Across the globe, emerging multidrug-resistant human and veterinary bacterial pathogens constitute a considerable public health issue and cost many lives every year
We hypothesized that adding an alkyl group to the tertiary amine of promazine to form a quaternary ammonium ion would prevent a compound from penetrating the because they can permeate the blood-brain (BBB)
The results showed that the increase in minimum inhibitory concentration (MIC) for fusidic acid (233-fold) was remarkably high compared with JBC 1847 (7fold) when tested against methicillin-resistant Staphylococcus aureus (MRSA) USA300 during the 23 days (Table 4)
Summary
Across the globe, emerging multidrug-resistant human and veterinary bacterial pathogens constitute a considerable public health issue and cost many lives every year. Among these pathogens, methicillin-resistant Staphylococcus aureus (MRSA) and thirdgeneration cephalosporin-resistant Escherichia coli are some of the most problematic (Coates et al, 2011; Cassini et al, 2019). The concentration of phenothiazines must be relatively high to obtain the synergistic effects, and studies have revealed that these compounds did not perform well as helper compounds when tested in vivo. The main purpose of this study was to chemically modify promazine, a compound belonging to the phenothiazine group, so that it would not permeate the BBB but retain its properties as an antimicrobial helper compound. A further purpose was to assess the properties and safety of the novel derivate using in vitro, in vivo, and in silico approaches
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