Abstract
Natural plant compounds, such as the chlorophyll a catabolites pheophorbide a (php) and pyropheophorbide a (pyp), are potentially active in the gastrointestinal tracts and manure of livestock as antimicrobial resistance-modifying agents through inhibition of bacterial efflux pumps. To investigate whether php, a known efflux pump inhibitor, and pyp influence bacterial resistance, we determined their long-term effects on the MICs of erythromycin for reference strains of clinically relevant indicator bacteria with macrolide or multidrug resistance efflux pumps. Pyp reduced the final MIC endpoint forStaphylococcus (S.) aureusandEscherichia (E.) coliby up to 1536 and 1024 μg erythromycin mL−1or 1.4- and 1.2-fold, respectively. Estimation of growth parameters ofS. aureusrevealed that pyp exerted an intrinsic inhibitory effect under anaerobic conditions and was synergistically active, thereby potentiating the effect of erythromycin and partially reversing high-level erythromycin resistance. Anaerobe colony counts of total and erythromycin-resistant bacteria from stored swine manure samples tended to be lower in the presence of pyp. Tylosin, php, and pyp were not detectable by HPLC in the manure or medium. This is the first study showing that pyp affects growth and the level of sensitivity to erythromycin ofS. aureus,E. coli, and anaerobic manure bacteria.
Highlights
Agricultural antimicrobial drug use is regarded a major driver of one of today’s foremost global public health challenges: more frequent clinical antimicrobial treatment failures due to resistant microorganisms [1,2,3,4]
The level of parental but not of induced resistance was higher in the Gram-negative strains than in the Gram-positives
Induction was higher under anaerobic than under aerobic conditions, with the maximum factor being 10240 (S. aureus)
Summary
Agricultural antimicrobial drug use is regarded a major driver of one of today’s foremost global public health challenges: more frequent clinical antimicrobial treatment failures due to resistant microorganisms [1,2,3,4]. In the U.S swine and other livestock production, much of the use of antimicrobials is nontherapeutic and/or occurs in the form of free-choice medicated feeds and water [1, 2, 5]. This results in exposures of the animals’ gastrointestinal tract and waste microbiota to inconsistent, often sublethal or subinhibitory concentrations [1, 6]. Soil amendment with manure presents a significant route of transmission of antimicrobial resistance from livestock bacteria to human clinical pathogens [4, 18,19,20,21,22,23,24]. MDR is a baseline resistance for the emergence of further resistance mechanisms, and, due to its physiological determination, it naturally persists [29,30,31,32]
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