Investigation of mixture toxicity of widely used drugs caffeine and ampicillin in the presence of an ACE inhibitor on bacterial growth using droplet-based microfluidic technique

Abstract

Droplet-based microfluidic technique is very suitable for a variety of screening processes. The cultivation within nanoliter segments and multidimensional microtoxicological screening of the Gram-negative bacterium Escherichia coli were studied under droplet-based microfluidic conditions. In order to evaluate the toxicity of the binary and ternary mixtures of antibiotic ampicillin and caffeine in the presence of the angiotensin-converting enzyme inhibitor captopril, a time-resolved optical double endpoint detection unit was applied. It included a microflow-through fluorimeter and photometer, which can simultaneously analyze changes in the endogenous autofluorescence signal and the cell density of E. coli cultivated inside 450-nl microfluid segments. As a result, strong nonlinear combination effects and a concentration-dependent antagonistic effect, as well as formation of activity summits on bolographic maps, were found. Our findings confirm the importance of multiparameter investigations for toxicological studies and could be taken into account in medical practice.

Droplet‐based microfluidics for microtoxicological studies

“…Life Sci. 2015, 00, 1-12 www.biotecvisions.com salts [64,82,83,88] as well as antibiotics [53,67,68,89,90] and other drugs [84,[91][92][93], and food components [80]. The obtained highly resolved dose/response functions from microfluidic investigations reflect roughly the same EC 50 values as observed in conventional screenings.…”

“…Complex responses, for example dose-dependent stimulation and compensation, and the formation of activity hills have been found in case of (i) chloramphenicol, phenolic uncoupler on the toxicity and activation of E. coli growth by caffeine [80] (Fig. 2G) and (ii) for the combination of caffeine with angiotensin-converting enzyme inhibitor captopril in the presence of ampicillin [91] ( Fig. 2H).…”

“…The spectrum of the analyzed organisms spans from bacteria as E. coli [53,57,67,74,[79][80][81] and Streptomyces [82], to eukaryotic microorganisms as Chlorella vulgaris [83], to multicellular organisms [64,65,84], animal cell lines [85], and human cells cultures such as human embryonic kidney (HEK) [86] and Jurkat cells [86,87]. The test substances involve heavy metal www.els-journal.com Eng.…”

Identification of response classes from heavy metal‐tolerant soil microbial communities by highly resolved concentration‐dependent screenings in a microfluidic system

“…; Cao et al . , ) allows the accurate determination of combinatorial effects and the differentiation between independent, additive, synergistic and complex interferences of effectors. Recently, this strategy was successfully applied for the characterization of the growth response of metal‐tolerant Streptomyces strains in response to combinations of heavy metals (Cao et al .…”

“…The applicability of this method was demonstrated for the bacterium E. coli , soil bacteria and soil bacterial communities (Cao et al 2013,b;K€ ursten et al 2014) as well as for eukaryotic and multicellular micro-organisms (Funfak et al 2007;Kuersten et al 2011). Beside highly resolved dose-response studies, the application of more complex flow rate programmes (Zheng, Tice & Ismagilov 2004;Gunther et al 2011;Cao et al 2012Cao et al , 2013a allows the accurate determination of combinatorial effects and the differentiation between independent, additive, synergistic and complex interferences of effectors. Recently, this strategy was successfully applied for the characterization of the growth response of metal-tolerant Streptomyces strains in response to combinations of heavy metals (Cao et al 2013,b).…”