piperine and Staphylococcal-Infections

Staphylococcus aureus is often found in orthopaedic infections and may be protected from commonly prescribed antibiotics by forming biofilms or growing intracellularly within osteoblasts. To investigate the effect of non-antibiotic compounds in conjunction with antibiotics to clear intracellular and biofilm forming S. aureus causing osteomyelitis. SAOS-2 osteoblast-like cell lines were infected with S. aureus BB1279. Antibiotics (vancomycin, VAN; and dicloxacillin, DICLOX), bacterial efflux pump inhibitors (piperine, PIP; carbonyl cyanide m-chlorophenyl hydrazone, CCCP), and bone morphogenetic protein (BMP-2) were evaluated individually and in combination to kill intracellular bacteria. We present direct evidence that after gentamicin killed extracellular planktonic bacteria and antibiotics had been stopped, seeding from the infected osteoblasts grew as biofilms. VAN was ineffective in treating the intracellular bacteria even at 10× MIC; however in presence of PIP or CCCP the intracellular S. aureus was significantly reduced. Bacterial efflux pump inhibitors (PIP and CCCP) were effective in enhancing permeability of antibiotics within the osteoblasts and facilitated killing of intracellular S. aureus. Confocal laser scanning microscopy (CLSM) showed increased uptake of propidium iodide within osteoblasts in presence of PIP and CCCP. BMP-2 had no effect on growth of S. aureus either alone or in combination with antibiotics. Combined application of antibiotics and natural agents could help in the treatment of osteoblast infected intracellular bacteria and biofilms associated with osteomyelitis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1086-1092, 2018.

Topics: Alkaloids; Anti-Bacterial Agents; Benzodioxoles; Bone Morphogenetic Protein 2; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cell Line, Tumor; Dicloxacillin; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Host-Pathogen Interactions; Humans; Microbial Sensitivity Tests; Osteoblasts; Osteomyelitis; Piperidines; Polyunsaturated Alkamides; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Piperine, a trans-trans-isomer of 1-piperoyl-piperidine, was tested in combination with mupirocin for antimicrobial activity against Staphylococcus aureus strains including meticillin-resistant S. aureus. The combination markedly reduced the MIC of mupirocin and also lowered the mutation frequency. Enhanced accumulation and efflux of ethidium bromide from wild-type and mutant (Mup(r)-1) strains in the presence of piperine indicated that inhibition of efflux could be a possible mechanism of potentiation of mupirocin activity by piperine. The combination of piperine with mupirocin in a dermal infection model of mice showed better in vivo efficacy when compared with the commercially available formulation of 2 % mupirocin.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Bacterial Proteins; Benzodioxoles; Disease Models, Animal; Drug Synergism; Enzyme Inhibitors; Ethidium; Female; Membrane Transport Proteins; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Mupirocin; Piperidines; Polyunsaturated Alkamides; Rodent Diseases; Staphylococcal Infections; Treatment Outcome