Abstract
The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13-substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against Mycobacterium, Candida albicans and Gram-positive bacteria, including naïve or resistant Bacillus cereus, Staphylococcus aureus and Streptococcus pyogenes with minimal inhibitory concentration (MIC) of 3.12 to 6.25 µM. Among the various Gram-negative strains tested, berberine’s derivatives were only found active on Helicobacter pylori and Vibrio alginolyticus (MIC values of 1.5–3.12 µM). Cytotoxicity assays performed on human cells showed that the antimicrobial berberine derivatives caused low toxicity resulting in good therapeutic index values. In addition, a mechanistic approach demonstrated that, contrarily to already known berberine derivatives causing either membrane permeabilization, DNA fragmentation or interacting with FtsZ protein, active derivatives described in this study act through inhibition of the synthesis of peptidoglycan or RNA. Overall, this study shows that these new berberine derivatives can be considered as potent and safe anti-bacterial agents active on human pathogenic microorganisms, including ones resistant to conventional antibiotics.
Highlights
According to the World Health Organization (WHO) “we are heading towards a post-antibiotic era in which common infections and minor injuries can once again kill” [1]
This technique based on the specific fluorescent labelling of bacterial followed by microscopic observation represents an alternative to radioactivity and was successfully used by others and us to evaluate the effect of various antibacterial agents on macromolecule synthesis [16,17]
The white whitescale scalebar baron onthe thebottom bottomright rightcorner cornercorresponds corresponds to to 44 μm. This technique based on the specific fluorescent labelling of bacterial followed by microscopic observation represents an alternative to radioactivity and wassynthesized successfullyand usedevaluated by others in and us to
Summary
According to the World Health Organization (WHO) “we are heading towards a post-antibiotic era in which common infections and minor injuries can once again kill” [1]. Antibiotics 2020, 9, x FOR PEER REVIEW. Antibiotic is rising dangerously worldwide, worldwide, threatening threatening our ability toour cure common infectious diseases that resistance is rising dangerously ability to cure common infectious become and sometimes impossible, to treat. Antibiotic is associated to higher medical diseasesharder, that become harder, and sometimes impossible, to resistance treat. Antibiotic resistance is associated costs, prolonged stays, andhospital increased mortality
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