Interactions of Antimcrobial Compounds with Selected Drugs used in the Clinical Management of Sickle Cell Disease (SCD)

Abstract

Though the promotion of resistant bacteria worldwide has mainly been attributed to the injudicious use of many antibiotics, the role of non-antimicrobial drugs used in the clinical management of pathological conditions of non-infectious diseases in the modulation of microbial drug resistance or susceptibility needs to be assessed. The effects of the antibiotic non-antibiotic drug-drug interactions against bacteria in SCD patients and in other chronic diseases cannot be overemphasized. The interactions of nine SCD management drugs and fifteen phenotype modulating compounds on the activities of 19 standard antimicrobials against clinical isolates of methicillin-resistant S. aureus (MRSA) and E. coli were investigated by the agar plate disc diffusion method. We also analyzed the effects of the compounds on ethidium bromide (EtBr) uptake and efflux in the bacterial cells, as well as their biofilm inhibitory and disrupting abilities. SCD drugs showed mostly resistance-inducing interactions with standard antibiotics particularly the cell wall inhibitors, amoxicillin and ampicillin and some few weak resistance breaking features mostly with gentamicin. The oral iron chelator, deferasirox and the opioid, morphine emerged as the key resistance-breaking (antibiotic enhancing) SCD drugs. Methotrexate, an anti-inflammatory and antifolate compound exhibited significant resistance inducing effects in both organisms. In E. coli, no SCD drug exceeded the intracellular ethidium bromide (EtBr) accumulation achieved by verapamil, the control for maximum accumulation. Hydroxyurea and paracetamol induced higher uptake of EtBr within MRSA relative to the control. A lower uptake of EtBr and higher rate efflux was associated with E. coli whereas MRSA generally showed very high accumulation levels and lower efflux rates. The most effective biofilm inhibiting abilities (approximately greater than 60%) was observed for methotrexate and pethidine against E. coli and none (greater than 50%) against MRSA. Deferasirox showed above 50% biofilm disrupting activity against E. coli biofilm and again none against MRSA biofilm. Biofilm formation in MRSA tended to be more robust than in E. coli. Our analyses of microbial stress responses to the unique antibiotic-non antibiotic interactions in further studies would reveal a number of endogenous resistance promoting genes that represent possible therapeutic targets in countering antimicrobial resistance.

Description

MPhil

Keywords

Antimcrobial Compounds, Selected Drugs, Clinical Management, Sickle Cell Disease (SCD)

Citation

Endorsement

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