Abstract
Nitazoxanide (NTZ) and other thiazolides are effective against intracellular protozoa’s, anaerobic or micro aerophilic bacteria, viruses and tumour cells. Concerning their potential effects against Escherichia coli, the published results are scarce and conflicting. In order to investigate whether thiazolides are effective against aerobically growing E. coli, we examined mutants of the TolC efflux system for their sensitivity to nitro thiazolides, including NTZ, and bromothiazolides. We determined the susceptibilities of tolC mutants to various thiazolides and found that tolC mutants of E. coli were susceptible to both nitro thiazolides and bromothiazolides indicating a mechanism of action different from nitro reduction. Moreover, we showed that thiazolides induced a spy:lacZ transcriptional fusion indicating that thiazolides generate stress in the bacterial envelope. Moreover, wild type strains became susceptible to thiazolides if the tolC efflux system was inhibited. Taken together, our results show that thiazolides are effective against E. coli if their export from the cells is impaired.
Highlights
In the mid-1990s, the thiazolides nitazoxanide (NTZ; AliniaTM, Romark Laboratories, FL, USA; Table 1) was approved by the FDA for treatment of persistent diarrhoea caused by Crypto sporidium parvum and Giardia duodenalis in children and adults [1]
We had found that NTZ was inhibitory for E. coli growth but only when a) the Giardianitro reductase GINR1 was expressed in the cells and b) when they were grown in semi-aerobic but not aerobic conditions [5] suggesting that bromo-thiazolides would not be effective
Our results show that tolC mutants of E. coli are susceptible to both nitro- and bromo-thiazolides
Summary
In the mid-1990s, the thiazolides nitazoxanide (NTZ; AliniaTM, Romark Laboratories, FL, USA; Table 1) was approved by the FDA for treatment of persistent diarrhoea caused by Crypto sporidium parvum and Giardia duodenalis in children and adults [1]. The respective in vitro, in vivo, and clinical studies have been reviewed elsewhere [2]. Susceptibility of G. duodenal is to thiazolides is dependent on the presence of a nitro group [3]. NTZ was investigated with respect to potential activities against anaerobic or micro aerophilic bacteria since resistance had appeared to the major current drug metronidazole [2]. In the anaerobic or micro aerophilic bacteria, reduction of the nitro group is regarded as the main mode of action [11,12]. In vitro studies indicate that NTZ and analogues may be active against aerobic bacteria such as Escherichia coli [13], Mycobacterium tuberculosis [14,15,16], and Staphylococcus sp. This is of particular interest since these pathogens often exhibit multidrug resistance against traditional antibiotics
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