Abstract
BackgroundTomatidine (TO) is a plant steroidal alkaloid that possesses an antibacterial activity against the small colony variants (SCVs) of Staphylococcus aureus. We report here the spectrum of activity of TO against other species of the Bacillales and the improved antibacterial activity of a chemically-modified TO derivative (FC04–100) against Listeria monocytogenes and antibiotic multi-resistant S. aureus (MRSA), two notoriously difficult-to-kill microorganisms.MethodsBacillus and Listeria SCVs were isolated using a gentamicin selection pressure. Minimal inhibitory concentrations (MICs) of TO and FC04–100 were determined by a broth microdilution technique. The bactericidal activity of TO and FC04–100 used alone or in combination with an aminoglycoside against planktonic bacteria was determined in broth or against bacteria embedded in pre-formed biofilms by using the Calgary Biofilm Device. Killing of intracellular SCVs was determined in a model with polarized pulmonary cells.ResultsTO showed a bactericidal activity against SCVs of Staphylococcus aureus, Bacillus cereus, B. subtilis and Listeria monocytogenes with MICs of 0.03–0.12 μg/mL. The combination of an aminoglycoside and TO generated an antibacterial synergy against their normal phenotype. In contrast to TO, which has no relevant activity by itself against Bacillales of the normal phenotype (MIC > 64 μg/mL), the TO analog FC04–100 showed a MIC of 8–32 μg/mL. Furthermore, FC04–100 showed a strong bactericidal activity against L. monocytogenes SCVs in kill kinetics experiments, while TO did not. The addition of FC04–100 (4 μg/mL) to a cefalexin:kanamycin (3:2) combination improved the activity of the combination by 32 fold against cefalexin and kanamycin-resistant MRSA strains. In combination with gentamicin, FC04–100 also exhibited a strong bactericidal activity against biofilm-embedded S. aureus. Also, FC04–100 and TO showed comparable intracellular killing of S. aureus SCVs.ConclusionsChemical modifications of TO allowed improvement of its antibacterial activity against prototypical S. aureus and of its bactericidal activity against L. monocytogenes. Antibacterial activities against such prominent pathogens could be useful to prevent Listeria contamination in the food chain or as treatment for MRSA infections.
Highlights
Tomatidine (TO) is a plant steroidal alkaloid that possesses an antibacterial activity against the small colony variants (SCVs) of Staphylococcus aureus
The Minimal inhibitory concentration (MIC) for TO ranged from 0.03 to 0.12 μg/mL against all the SCVs tested from the species S. aureus, L. monocytogenes, B. cereus and B. subtilis, whereas TO showed no activity (MIC > 64 μg/mL) against the prototypic strains including S. epidermidis (Table 1)
Strains of the normal phenotype were more susceptible to GEN compared to their SCV derivatives; this was expected because aminoglycosides (e.g., GEN) require an active respiratory chain and the proton-motive force in order to penetrate the bacterium
Summary
Tomatidine (TO) is a plant steroidal alkaloid that possesses an antibacterial activity against the small colony variants (SCVs) of Staphylococcus aureus. We report here the spectrum of activity of TO against other species of the Bacillales and the improved antibacterial activity of a chemically-modified TO derivative (FC04–100) against Listeria monocytogenes and antibiotic multi-resistant S. aureus (MRSA), two notoriously difficult-to-kill microorganisms. The Bacillales are divided into the genus of Staphylococcus, Listeria and Bacillus. A number of bacterial species such as Listeria spp. and Bacillus spp. can contaminate food and cause infections in humans [1]. Listeria monocytogenes, L. ivanovii, and Bacillus cereus can cause listeriosis [2] and food poisoning [3]. Staphylococci are divided in coagulase-positive species, Staphylococcus aureus being the most clinically relevant of this group, and coagulasenegative species, such as S. epidermidis, the most prevalent pathogen associated with infections of implanted medical devices [5]. The prevalence of methicillin-resistant S. aureus (MRSA) has steadily increased over the recent years, in hospitals and in the community [7], and in veterinary medicine and livestock [8,9,10]
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