Interactions of Antimcrobial Compounds with Selected Drugs used in the Clinical Management of Sickle Cell Disease (SCD)
Date
2018-07
Authors
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Journal ISSN
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Publisher
University of Ghana
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)