Molecular basis of metronidazole resistance in pathogenic bacteria and protozoa

Land, Kirkwood M.; Johnson, Patricia J.

doi:10.1054/drup.1999.0104

Cited by 83 publications

(76 citation statements)

References 62 publications

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“…Mz resistance is functionally heterogeneous, with several causative mechanisms for each of the target microbes and between different microbes (7,24). For example, resistance in Giardia involves down-regulation of nitro drug-activating systems, including different reductases and redox proteins and metabolites (11,25), whereas Trichomonas also produces resistance proteins that directly detoxify nitro drugs (12) and Bacteroides has transporters that can remove nitro drugs from the cell (26).…”

Section: Discussionmentioning

confidence: 99%

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Miyamoto¹,

Kalisiak

Korthals

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.infectious diseases | antibiotics | medicinal chemistry

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Section: Discussionmentioning

confidence: 99%

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Miyamoto¹,

Kalisiak

Korthals

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Klinik olarak birbirini anımsatmaktan bulaş yollarına benzerliklerin tartışıldığı çalışmalardan (25); yineleyen karın ağrılı çocuklarda ve dispeptik hasta gruplarında anlamlı birlikteliklerinin saptandığı (4-6, 26), herhangi birinin sebep olduğu gastrit durumlarının bir diğerine karşı kişiyi yatkın (predispozan) kıldığının savunulduğu (27,28), metronidazol rezistansındaki sinerji olasılık-larının raporlandığı (29) ve gastrointestinal metaplaziye yol açtık-ları patogenetik senaryolarının deneysel kanıtlandığı (30) çalışmalara kadar pek çok durum için iki patojenin arasındaki ilişki ortaya konmuştur. Bu çalışmada H. pylori'li hastaların her ikisinde de G. intestinalis saptanmıştır.…”

Section: Discussionunclassified

The Prevalence of Intestinal Parasites in Children with Helicobacter pylori Gastritis Evaluated Retrospectively

Uğraş¹,

Miman²

2014

TurkiyeParazitolDerg

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ÖZET Amaç: Gelişmekte olan ülkelerde H. pylori enfeksiyonu gelişmiş ülkelere göre daha sık ve daha erken yaşta görülmektedir. Etyopatogenezinde kalabalık ailelerde yaşam, annenin eğitim seviyesinin düşük olması, düşük ekonomik gelir, kirli içme suları gibi faktörlerin varlığında daha sık görüldüğü bildirilmiştir. Sosyoekonomik durumu iyi olmayan bölgelerde intestinal parazitozların da daha sık görüldüğü bilinmektedir. Bu çalışmada amaç, H. pylori gastriti olduğu endoskopik ve histopatolojik olarak ispatlanmış hastalarda intestinal parazit sıklığınının incelenmesidir. ABSTRACT Objective: H. pylori infection is more frequent and is seen in younger ages in developing countries when compared to developed countries. Etiopathogenetic factors include living in crowded families, low educational level of mother, low income and infected drinking water.Intestinal parasites are more frequent in low socioeconomical populations. In this study, it was aimed to determine the prevalence of intestinal parasite in patients with H. pylori gastritis proven with endoscopic and histopathological study. Methods: Parasitology laboratory results of children who had undergone upper gastrointestinal system endoscopy (UGE) and were proved to have H. pylori gastritis were evaluated retrospectively. Stool samples were examined using native lugol and precipitation by formol ethyl acetate methods.

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“…The lack of research into basic Giardia biology and a lack of effective and affordable methods of treatment have led the World Health Organization (WHO) to name giardiasis a neglected disease (35). As Giardia continues to become more resistant to the drug metronidazole, it becomes increasingly important to discover new ways to treat this common parasitic infection (3,28,39).…”

Section: G Iardia Intestinalis Is a Parasitic Protist That Causes Giamentioning

confidence: 99%

The Giardia Median Body Protein Is a Ventral Disc Protein That Is Critical for Maintaining a Domed Disc Conformation during Attachment

Woessner

Dawson

2012

Eukaryot Cell

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Giardia has unique microtubule structures, including the ventral disc, the primary organelle of attachment to the host, and the median body, a structure of undefined function. During attachment, the ventral disc has a domed conformation and enables Giardia to attach to the host intestinal epithelia within seconds. The mechanism of attachment via the ventral disc and the overall structure, function, and assembly of the ventral disc are not well understood. Our recent proteomic analysis of the ventral disc indicated that the median body protein (MBP), previously reported to localize exclusively to the median body, was primarily localized to the ventral disc. Using high-resolution light and electron microscopy, we confirm that the median body protein localizes primarily to the overlap zone of the ventral disc. The MBP also occasionally localized to the median body during prophase. To define the contribution of MBP to the ventral disc structure, we depleted MBP using an anti-MBP morpholino. We found that the ventral disc was no longer able to form properly and that the disc structure often had an aberrant nondomed or flattened horseshoe conformation. The ability of attached anti-MBP morpholino-treated trophozoites to withstand shear forces and normal forces was significantly decreased. Most notably, the plasma membrane contacts with the surface, including those of the bare area, were defective after the anti-MBP knockdown. To our knowledge, this is the first ventral disc protein whose depletion directly alters ventral disc structure, confirming that the domed ventral disc conformation is important for robust attachment.

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Molecular basis of metronidazole resistance in pathogenic bacteria and protozoa

Cited by 83 publications

References 62 publications

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

The Prevalence of Intestinal Parasites in Children with Helicobacter pylori Gastritis Evaluated Retrospectively

The Giardia Median Body Protein Is a Ventral Disc Protein That Is Critical for Maintaining a Domed Disc Conformation during Attachment

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