Interactions of Antimicrobial Compounds with Selected Drugs Used in the Clinical Management of Sickle Cell Disease (SCD)
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Date
2018-07
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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 antibioticnon-
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 GGP E120) and E. coli (E.
coli GGP E100) were investigated by pairwise drug combinations between SCD
drugs/phenotypic compounds and antimicrobial agents using the agar plate disc diffusion
method. The comparative effects of the SCD drugs/PMCs on ethidium bromide (EtBr) uptake
and efflux in the bacterial cells relative to verapamil were detected by measuring
fluorescence of intracellular EtBr. SCD drugs and PMCs biofilm inhibitory and disrupting
abilities were analyzed by reading absorbencies of crystal violet stained biofilms. Bacterial
strains were obtained from the bacteriology departments of the Noguchi Memorial Institute
for Medical Research, University of Ghana, Accra.
In the preliminary pairwise combination screen by disc diffusion, SCD drugs produced
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 opioid medication, morphine emerged as a key resistance-breaking
(antibiotic enhancing) SCD drug. Methotrexate, an anti-inflammatory and anti-folate
compound generated significant interactions with antibiotics against both organisms.
Resistance breaking and resistance inducing effects were characterized as increase and decrease in zones of inhibition by four millimetres or more respectively, compared to zones
produced in the absence of SCD drug.
In E. coli, no SCD drug exceeded the accumulated intracellular ethidium bromide (EtBr)
level achieved by verapamil, the control for maximum accumulation. Hydroxyurea and
paracetamol induced higher uptake of EtBr within MRSA relative to verapamil. Results were
analyzed using the fluorescence value of verapamil control as standard to assess and compare
the effects of the SCD drugs, taking into consideration the overlapping of error bars.
Generally, all SCD drugs showed higher rates of efflux inhibition (low efflux activity)
relative to the no drug treatment control (bacterial cells and EtBr only) in both organisms,
following the course of the line curves. Efflux activities of SCD drugs were not significantly
different from verapamil with the exception of deferasirox and methotrexate in E. coli. In
MRSA, efflux activities of methotrexate, morphine, ibuprofen and paracetamol treated cells
were not significantly distinct relative to efflux activity of verapamil, the control for
minimum rate of efflux.
Using a 50% value of biofilm formed in the compound free medium as a cut-off to analyze
the effects of SCD drugs, 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. Overlapping of error
bars representing standard error of the mean was carefully considered in the analyses. Biofilm
formation and integrity tended to be more robust in MRSA than in E. coli.
Extracts from four fungal isolates – SBF 052, SBF 062, TEF 246 and TEF 256 showed
antibacterial activities against both E. coli and MRSA in a preliminary disc diffusion assay. The resistance-inducing interactions and few resistance-breaking interactions generated by
SCD drugs to the antibiotics against both bacterial strains could not be attributed to their
effects on efflux or biofilm formation and thus, the need for further investigations to establish
the molecular mechanisms causing such interactions.
Further investigations are also necessary to provide healthcare providers with information on
what antibiotics to prescribe for certain chronic disease patients who are continually taking
particular management medications.
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. Molecular Cell Biology of Infectious Diseases
Keywords
Bacterial Infections, Sickle Cell Disease, Fungi, SCD Drugs