Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent

Ramoplanin, a novel antibiotic with activity against aerobic and anaerobic Gram-positive bacteria, acts to prevent cell wall peptidoglycan formation by binding to a key intermediate moiety, lipid II. It has been fast-tracked by the US FDA for the prevention of enterococcal infections and the treatment of Clostridium difficile. The minimum inhibitory concentration_90s have been ≤1.0 µg/ml against Gram-positive organisms examined. In carriers of vancomycin-resistant enterococci, a double-blind, placebo-controlled Phase II trial of two doses of ramoplanin versus placebo showed proof of concept. A second Phase II trial also demonstrated the equivalence of ramoplanin compared with vancomycin for the treatment of C. difficile colitis. The clinical value and place in therapy of ramoplanin is dependent upon the results of Phase III trials addressing its utility in suppressing carriage of target organisms in the gastrointestinal tract or in the nares.     

Genome analysis of NDM-1 producing Morganella morganii clinical isolate

Objective: To analyze the resistome and virulence genes of Morganella morganii F675, a multidrug-resistant clinical isolate using whole genome sequencing (WGS). Methods: M. morganii F675 was isolated from a patient from Jerusalem, Israel. WGS was performed using both 454 and SOLiD sequencing technologies. Analyses of the bacterial resistome and other virulence genes were performed in addition to comparison with other available M. morganii genomes. Results: The assembled sequence had a genome size of 4,127,528 bp with G+C content of 51%. The resistome consisted of 13 antibiotic resistance genes including bla_NDM-1 located in a plasmid likely acquired from Acinetobacter spp. Moreover, we characterized for the first time the whole lipid A biosynthesis pathway in this species along with the O-antigen gene cluster, the urease gene cluster and several other virulence genes. Conclusion: The WGS analysis of this pathogen further provides insight into its pathogenicity and resistance to antibiotics.     

Host–microbe interaction: mechanisms of defensin deficiency in Crohn’s disease

Defensins are endogenous antibiotics with microbicidal activity against Gram-negative and -positive bacteria, fungi, enveloped viruses and protozoa. A disturbed antimicrobial defense, as provided by Paneth and other epithelial cell defensins, seems to be a critical factor in the pathogenesis of Crohn’s disease, an inflammatory disease of the intestinal tract. Different direct and indirect mechanisms leading to a breakdown of antimicrobial barrier function include direct changes in defensin gene numbers (e.g., copy number polymorphism), genetic mutations in pattern-recognition receptors (e.g., nucleotide-binding oligomerization domain 2) and, as described recently, a differentiation problem of epithelial stem cells mediated by the wingless type (Wnt) pathway. Knowledge regarding the regulation and biology of defensins provides an attractive target to open up new therapeutic avenues.     

Colistin: an update on the antibiotic of the 21st century

The emergence of multidrug-resistant Gram-negative bacteria that cause nosocomial infections is a growing problem worldwide. Colistin was first introduced in 1952 and was used until the early 1980s for the treatment of infections caused by Gram-negative bacilli. In vitro, colistin has demonstrated excellent activity against various Gram-negative rod-shaped bacteria, including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Recent clinical findings regarding colistin activity, pharmacokinetic properties, clinical uses, emerging resistance, toxicities and combination therapy have been reviewed. Recent approaches to the use of colistin in combination with other antibiotics hold promise for increased antibacterial efficacy. It is probable that colistin will be the ‘last-line’ therapeutic drug against multidrug-resistant Gram-negative pathogens in the 21st century.     

2012年我院院内痰培养阳性菌检出率统计分析

目的找出2012年芜湖市第五人民医院住院患者痰培养阳性菌检出率低的原因,以便改进操作方法。方法回顾性分析2012年本院肺部感染住院患者痰培养检测结果。结果2012年本院院内痰培养标本共计952例。男613例,女339例,中位年龄56岁;阳性菌标本共计107例,男76例,女31例,中位年龄62岁,阳性菌标本检出率为11．2％。铜绿假单胞菌占阳性检出菌总数的31．8％,大肠埃希菌占阳性检出菌总数的15．9％。结论本院痰培养阳性菌检出率低,需要尽快改进操作方法以提高阳性标本检出率。     

Mechanism of action and initial evaluation of a membrane active all-D-enantiomer antimicrobial peptidomimetic

Development of therapy against infections caused by antibiotic-resistant pathogens is a major unmet need in contemporary medicine. In previous work, our group chemically modified an antimicrobial peptidomimetic motif for targeted applications against cancer and obesity. Here, we show that the modified motif per se is resistant to proteolytic degradation and is a candidate antiinfective agent. We also show that the susceptibility of microorganisms to the drug is independent of bacterial growth phase. Moreover, this peptidomimetic selectively interferes with the integrity and function of the microbial surface lipid bilayer, data indicative that bacterial death results from membrane disruption followed by dissipation of membrane potential. Finally, we demonstrate two potential translational applications: use against biofilms and synergy with antibiotics in use. In summary, we introduce the mechanism of action and the initial evaluation of a prototype drug and a platform for the development of D-enantiomer antimicrobial peptidomimetics that target bacterial membranes of certain Gram-negative problem pathogens with promising translational applications.     

Liposome division by a simple bacterial division machinery

We previously reconstituted Z rings in tubular multilamellar liposomes with FtsZ-YFP-mts, where mts is a membrane-targeting amphiphilic helix. These reconstituted Z rings generated a constriction force but did not divide the thick-walled liposomes. Here we developed a unique system to observe Z rings in unilamellar liposomes. FtsZ-YFP-mts incorporated inside large, unilamellar liposomes formed patches that produced concave distortions when viewed at the equator of the liposome. When viewed en face at the top of the liposome, many of the patches were seen to be small Z rings, which still maintained the concave depressions. We also succeeded in reconstituting the more natural, two-protein system, with FtsA and FtsZ-YFP (having the FtsA-binding peptide instead of the mts). Unilamellar liposomes incorporating FtsA and FtsZ-YFP showed a variety of distributions, including foci and linear arrays. A small fraction of liposomes had obvious Z rings. These Z rings could constrict the liposomes and in some cases appeared to complete the division, leaving a clear septum between the two daughter liposomes. Because complete liposome divisions were not seen with FtsZ-mts, FtsA may be critical for the final membrane scission event. We demonstrate that reconstituted cell division machinery apparently divides the liposome in vitro.     

Infective endocarditis caused by Granulicatella adiacens

Granulicatella adiacens, a recently nomenclatured bacterium, was considered as one of the nutritionally variant streptococci (NVS) and is a mouth commensal. It is redesignated as a streptococcus like bacterium since it differs from streptococci. We report a case of infective endocarditis (IE) caused by this fastidious and unusual bacteria in a 63-year-old man with rheumatic valvular heart disease. G. adiacens was isolated from four of his blood culture samples, which was sensitive to beta lactams, moderately sensitive to gentamicin and resistant to erythromycin and co-trimoxazole. Patient recovered completely on treatment with high dose of ampicillin and gentamicin for 28 days.     

Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes

Mitochondria and chloroplasts are major sources of free radical generation in living organisms. Because of this, these organelles require strong protection from free radicals and associated oxidative stress. Melatonin is a potent free radical scavenger and antioxidant. It meets the criteria as a mitochondrial and chloroplast antioxidant. Evidence has emerged to show that both mitochondria and chloroplasts may have the capacity to synthesize and metabolize melatonin. The activity of arylalkylamine N‐acetyltransferase (AANAT), the reported rate‐limiting enzyme in melatonin synthesis, has been identified in mitochondria, and high levels of melatonin have also been found in this organelle. From an evolutionary point of view, the precursor of mitochondria probably is the purple nonsulfur bacterium, particularly, Rhodospirillum rubrum, and chloroplasts are probably the descendents of cyanobacteria. These bacterial species were endosymbionts of host proto‐eukaryotes and gradually transformed into cellular organelles, that is, mitochondria and chloroplasts, respectively, thereby giving rise to eukaryotic cells. Of special importance, both purple nonsulfur bacteria (R. rubrum) and cyanobacteria synthesize melatonin. The enzyme activities required for melatonin synthesis have also been detected in these primitive species. It is our hypothesis that mitochondria and chloroplasts are the original sites of melatonin synthesis in the early stage of endosymbiotic organisms; this synthetic capacity was carried into host eukaryotes by the above‐mentioned bacteria. Moreover, their melatonin biosynthetic capacities have been preserved during evolution. In most, if not in all cells, mitochondria and chloroplasts may continue to be the primary sites of melatonin generation. Melatonin production in other cellular compartments may have derived from mitochondria and chloroplasts. On the basis of this hypothesis, it is also possible to explain why plants typically have higher melatonin levels than do animals. In plants, both chloroplasts and mitochondria likely synthesize melatonin, while animal cells contain only mitochondria. The high levels of melatonin produced by mitochondria and chloroplasts are used to protect these important cellular organelles against oxidative stress and preserve their physiological functions. The superior beneficial effects of melatonin in both mitochondria and chloroplasts have been frequently reported.