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"Lewis, Kim"
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Seymour and Henry
Seymour and Henry love to play, but when it is time to go home, the ducklings run away from Mommy. Can the two ducklings find their way back to her? And what will Mommy do then?
Book
Alternative positioning method for the superior–inferior axial shoulder projection – the Lewis modification
The superior–inferior (SI) axial shoulder view is an important part of shoulder imaging. It provides a true orthogonal view to the anterior–posterior (AP) shoulder projection and is a supplementary view to the lateral scapula view. When positioned correctly, the glenohumeral joint is visualised with the superior and inferior aspects of the glenoid superimposed to demonstrate the true relationship between the glenoid and humerus. Positioning for the SI axial view is challenging. Often the glenoid is not superimposed on resulting images, and the glenohumeral relationship cannot be assessed accurately. Some positioning texts do not demonstrate the SI axial view, opting instead for the inferior–superior (IS) view. When the SI axial view is included, bony landmarks are not provided to assist medical imaging technologists (MITs) with accurate positioning. This paper outlines a proposed modification using bony landmarks that can assist MITs in positioning their patients for this important view and obtain diagnostic images that demonstrate the glenoid in true profile. The superior‐inferior (SI) axial shoulder view is an important part of shoulder imaging. When positioned correctly the gleno‐humeral joint is visualised with the superior and inferior aspects of the glenoid superimposed to demonstrate the true relationship between the glenoid and humerus. This paper outlines a proposed modification using bony landmarks that can assist MITs in positioning their patients for this important view and obtain diagnostic images that demonstrate the glenoid in true profile.
Journal Article
Batman, the Dark Knight detective
\"In these stories that immediately followed BATMAN: YEAR ONE, the Caped Crusader learns what kind of compromises he must make to be the hero that Gotham City truly needs. As he battles against the deadly Reaper, the city's first vigilante hero, Batman must work with the man who murdered his parents and a cadre of mob bosses to protect Gotham City.\"-- Provided by publisher.
Book
Platforms for antibiotic discovery
Key Points
The pace of antibiotic discovery has slowed down while resistance to bacteria is increasing.
Biofilms harbouring drug-tolerant persisters often lead to untreatable chronic infections.
Looking for untapped sources, such as uncultured bacteria, and developing rapid dereplication are likely to resuscitate the natural product discovery platform.
A focus on species-specific compounds will provide a discovery platform, as the probability of finding such molecules is higher than the probability of discovering broader-spectrum antimicrobial compounds.
Establishing rules that guide the penetration of molecules into bacteria will revive the rational design and high-throughput screening of synthetic compounds.
Prodrugs that form reactive molecules within bacterial cells are capable of broad-spectrum and sterilizing activity.
Re-establishing effective platforms for antibiotic discovery is crucial for combating the growing threats from antibiotic resistance. Here, Lewis discusses the lessons learned from the golden era of antibiotic discovery and reasons for the failure of previous platforms, and proposes strategies to create new platforms or revitalize old ones, including harnessing untapped sources of natural products as well as developing species-selective and prodrug antibiotics.
The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.
Journal Article
Ciprofloxacin Causes Persister Formation by Inducing the TisB toxin in Escherichia coli
Bacteria induce stress responses that protect the cell from lethal factors such as DNA-damaging agents. Bacterial populations also form persisters, dormant cells that are highly tolerant to antibiotics and play an important role in recalcitrance of biofilm infections. Stress response and dormancy appear to represent alternative strategies of cell survival. The mechanism of persister formation is unknown, but isolated persisters show increased levels of toxin/antitoxin (TA) transcripts. We have found previously that one or more components of the SOS response induce persister formation after exposure to a DNA-damaging antibiotic. The SOS response induces several TA genes in Escherichia coli. Here, we show that a knockout of a particular SOS-TA locus, tisAB/istR, had a sharply decreased level of persisters tolerant to ciprofloxacin, an antibiotic that causes DNA damage. Step-wise administration of ciprofloxacin induced persister formation in a tisAB-dependent manner, and cells producing TisB toxin were tolerant to multiple antibiotics. TisB is a membrane peptide that was shown to decrease proton motive force and ATP levels, consistent with its role in forming dormant cells. These results suggest that a DNA damage-induced toxin controls production of multidrug tolerant cells and thus provide a model of persister formation.
Journal Article
Definitions and guidelines for research on antibiotic persistence
Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.Antibiotic persistence contributes to the survival of bacteria during antibiotic treatment. In this Consensus Statement, scientists working on the response of bacteria to antibiotics define antibiotic persistence and provide practical guidance on how to study bacterial persisters.
Journal Article
Characterization and Transcriptome Analysis of Mycobacterium tuberculosis Persisters
Tuberculosis continues to be a major public health problem in many parts of the world. Significant obstacles in controlling the epidemic are the length of treatment and the large reservoir of latently infected people. Bacteria form dormant, drug-tolerant persister cells, which may be responsible for the difficulty in treating both acute and latent infections. We find that in Mycobacterium tuberculosis , low numbers of drug-tolerant persisters are present in lag and early exponential phases, increasing sharply at late exponential and stationary phases to make up ~1% of the population. This suggests that persister formation is governed by both stochastic and deterministic mechanisms. In order to isolate persisters, an exponentially growing population was treated with d -cycloserine, and cells surviving lysis were collected by centrifugation. A transcriptome of persisters was obtained by using hybridization to an Affymetrix array. The transcriptome shows downregulation of metabolic and biosynthetic pathways, consistent with a certain degree of dormancy. A set of genes was upregulated in persisters, and these are likely involved in persister formation and maintenance. A comparison of the persister transcriptome with transcriptomes obtained for several in vitro dormancy models identified a small number of genes upregulated in all cases, which may represent a core dormancy response. IMPORTANCE It is estimated that every third person on the planet is infected with Mycobacterium tuberculosis . The two major problems in controlling M. tuberculosis are the length of the treatment and the large reservoir of latently infected people. Dormant persister cells may be responsible for both problems. We find that M. tuberculosis produces persisters in vitro in a growth phase-dependent manner. Persisters were isolated from an exponentially growing population, and their transcriptome shows a distinct pattern of dormancy. These results give the first insight into M. tuberculosis persisters and point to possible mechanisms responsible for their formation. It is estimated that every third person on the planet is infected with Mycobacterium tuberculosis . The two major problems in controlling M. tuberculosis are the length of the treatment and the large reservoir of latently infected people. Dormant persister cells may be responsible for both problems. We find that M. tuberculosis produces persisters in vitro in a growth phase-dependent manner. Persisters were isolated from an exponentially growing population, and their transcriptome shows a distinct pattern of dormancy. These results give the first insight into M. tuberculosis persisters and point to possible mechanisms responsible for their formation.
Journal Article
Bacterial persisters are a stochastically formed subpopulation of low-energy cells
Persisters represent a small subpopulation of non- or slow-growing bacterial cells that are tolerant to killing by antibiotics. Despite their prominent role in the recalcitrance of chronic infections to antibiotic therapy, the mechanism of their formation has remained elusive. We show that sorted cells of Escherichia coli with low levels of energy-generating enzymes are better able to survive antibiotic killing. Using microfluidics time-lapse microscopy and a fluorescent reporter for in vivo ATP measurements, we find that a subpopulation of cells with a low level of ATP survives killing by ampicillin. We propose that these low ATP cells are formed stochastically as a result of fluctuations in the abundance of energy-generating components. These findings point to a general “low energy” mechanism of persister formation.
Journal Article
A new antibiotic selectively kills Gram-negative pathogens
The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens
1
,
2
. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds
3
,
4
. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s
2
. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on
Photorhabdus
symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of
Photorhabdus
isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.
Journal Article