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 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) 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 resistancebreaking

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 resistanceinducing

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

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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-nonantibiotic

interactions in further studies would reveal a number of endogenous resistancepromoting

genes that represent possible therapeutic targets in countering antimicrobial

resistance.