Hospital-acquired infections: diseases with increasingly limited therapies.

Swartz, Morton N.

doi:10.1073/pnas.91.7.2420

Cited by 202 publications

(147 citation statements)

References 53 publications

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“…Nosocomial infections increased sharply in the United States between 1980 and the present day, and seven leading pathogen groups have accounted for most of this increase: Escherichia coli, Staphylococcus aureus, coagulase-negative staphylococci, streptococci, Enterococcus faecium, Pseudomonas aeruginosa, and Candida albicans. Four of these seven pathogens are Gram-positive bacteria, and resistance to commonly used antibiotics has emerged in all of them (2). Given the speed with which such antibiotic resistance is spreading, it is not difficult to foresee a time when our most serious infectious threats may become largely untreatable.…”

mentioning

confidence: 99%

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Hamburger

Hoertz

Lee

et al. 2009

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

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The glycodepsipeptide antibiotic ramoplanin A2 is in late stage clinical development for the treatment of infections from Grampositive pathogens, especially those that are resistant to first line antibiotics such as vancomycin. Ramoplanin A2 achieves its antibacterial effects by interfering with production of the bacterial cell wall; it indirectly inhibits the transglycosylases responsible for peptidoglycan biosynthesis by sequestering their Lipid II substrate. Lipid II recognition and sequestration occur at the interface between the extracellular environment and the bacterial membrane. Therefore, we determined the structure of ramoplanin A2 in an amphipathic environment, using detergents as membrane mimetics, to provide the most physiologically relevant structural context for mechanistic and pharmacological studies. We report here the X-ray crystal structure of ramoplanin A2 at a resolution of 1.4 Å. This structure reveals that ramoplanin A2 forms an intimate and highly amphipathic dimer and illustrates the potential means by which it interacts with bacterial target membranes. The structure also suggests a mechanism by which ramoplanin A2 recognizes its Lipid II ligand.glycolipodepsipeptide ͉ mechanism ͉ vancomycin resistance

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confidence: 99%

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Hamburger

Hoertz

Lee

et al. 2009

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

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“…degradable antibiotics | ribosomes | resistance | species-specific antibiotics | Gram-positive T he emergence of multidrug-resistant pathogenic strains of Enterococci, Staphylococci, and Streptococci Gram-positive bacteria poses a serious threat to modern medicine (1)(2)(3). Several classes of antibiotics inhibit protein synthesis by targeting functional sites of the bacterial ribosome.…”

mentioning

confidence: 99%

Avilamycin and evernimicin induce structural changes in rProteins uL16 and CTC that enhance the inhibition of A-site tRNA binding

Krupkin

Wekselman

Matzov

et al. 2016

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

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Two structurally unique ribosomal antibiotics belonging to the orthosomycin family, avilamycin and evernimicin, possess activity against Enterococci, Staphylococci, and Streptococci, and other Gram-positive bacteria. Here, we describe the high-resolution crystal structures of the eubacterial large ribosomal subunit in complex with them. Their extended binding sites span the A-tRNA entrance corridor, thus inhibiting protein biosynthesis by blocking the binding site of the A-tRNA elbow, a mechanism not shared with other known antibiotics. Along with using the ribosomal components that bind and discriminate the A-tRNA-namely, ribosomal RNA (rRNA) helices H89, H91, and ribosomal proteins (rProtein) uL16-these structures revealed novel interactions with domain 2 of the CTC protein, a feature typical to various Gram-positive bacteria. Furthermore, analysis of these structures explained how single nucleotide mutations and methylations in helices H89 and H91 confer resistance to orthosomycins and revealed the sequence variations in 23S rRNA nucleotides alongside the difference in the lengths of the eukaryotic and prokaryotic α1 helix of protein uL16 that play a key role in the selectivity of those drugs. The accurate interpretation of the crystal structures that could be performed beyond that recently reported in cryo-EM models provide structural insights that may be useful for the design of novel pathogen-specific antibiotics, and for improving the potency of orthosomycins. Because both drugs are extensively metabolized in vivo, their environmental toxicity is very low, thus placing them at the frontline of drugs with reduced ecological hazards. degradable antibiotics | ribosomes | resistance | species-specific antibiotics | Gram-positive

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“…1 Bacterial translocation can occur if the intact environment is compromised, thus leading to the provocation of several cytokine networks and multiple organ failure in the end. [2][3][4][5] Especially, liver transplant recipients usually have a long history of liver disease and suffer portal hypertension, which leads to malnutrition. 6 Therefore, the mucosa of their bowel could be atrophic and more susceptible to bacterial translocation, which leads to endotoxenemia and multi-organ failure.…”

mentioning

confidence: 99%

Perioperative synbiotic treatment to prevent infectious complications in patients after elective living donor liver transplantation: a prospective randomized study

Eguchi

Takatsuki

Hidaka

et al. 2011

The American Journal of Surgery

107

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Hospital-acquired infections: diseases with increasingly limited therapies.

Cited by 202 publications

References 53 publications

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

Avilamycin and evernimicin induce structural changes in rProteins uL16 and CTC that enhance the inhibition of A-site tRNA binding

Perioperative synbiotic treatment to prevent infectious complications in patients after elective living donor liver transplantation: a prospective randomized study

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