P20 Identification and detailed bio-evaluation of malabaricone B as a potent antistaphylococcal lead

Abstract

BackgroundThe dearth of antimicrobials to treat MDR infections has led to search for novel moieties with potent activity. The most suitable compounds have been derived from mainly natural sources. In this context, the current study focused on identification and determination of antistaphylococcal activity of malabaricone B (MB), one of the naturally abundant secondary metabolites (malabaricones A–D) present in the Myristicaceae family. Malabaricones have previously been reported to possess various biological activities including antimicrobial activity but prospects of its effective utilization against Staphylococcus aureus infections in particular have not been explored in detail to the best of our knowledge.MethodsMalabaricones (A–D) were screened against an ESKAPE pathogen panel via broth microdilution assays. The hit compounds were then tested against Vero cells via MTT assays to determine their selectivity index. As the next step, their activity against clinical drug-resistant strains was evaluated. Further, time–kill kinetics against S. aureus were determined along with the ability to synergize with approved drugs via chequerboard assays, which was further validated via combination time–kill kinetics assays. The hit compound's in vitro post-antibiotic effect (PAE) and propensity to generate resistance to S. aureus was determined. Its activity against intracellular S. aureus in a J774 macrophage model of infection and ability to eradicate pre-formed S. aureus biofilms in vitro was ascertained. Finally, the hit compound's in vivo efficacy was determined in a murine neutropenic S. aureus thigh infection model.ResultsAmongst the hits identified, MB demonstrated a potent in vitro antistaphylococcal profile including equipotent activity against clinical MDR S. aureus and Enterococcus sp. with MIC 1–2 mg/L. MB exhibited concentration-dependent bactericidal activity with complete killing at 5 × MIC within 15 min of exposure with no regrowth up to 24 h. MB also displayed PAE of ∼22 h at 10 × MIC. It also has very low propensity for generation of resistance to S. aureus ATCC 29213. MB significantly eradicated pre-formed S. aureus biofilms and reduced intracellular S. aureus in the J774 macrophage infection model as well. MB strongly synergized with gentamicin at 1 × MIC in vitro with complete killing at 24 h as compared with untreated S. aureus. MB also possessed significant in vivo activity against S. aureus at 50 mg/kg BID dose with ∼0.5 log10 cfu/g reduction in thigh compared with untreated mice.ConclusionsMB demonstrates the potential to be further developed for infections caused by S. aureus owing to its excellent in vitro and in vivo activity.