Publisher Health

Researchers have identified a critical mechanism that allows deadly bacteria to gain resistance to antibiotics.
The findings offer a potential new drug target in the search for effective new antibiotics as we face the growing threat of antimicrobial resistance (AMR) and infections caused by bacterial pathogens.
The study investigated quinolone antibiotics which are used to treat a range of bacterial infections, including TB (tuberculosis). Quinolones work by inhibiting bacterial enzymes, gyrase and topoisomerase IV, thereby preventing DNA replication and RNA synthesis essential to growth.
They are highly-successful antimicrobial agents widely used in current medicine, however bacterial resistance to them and other treatments is a serious problem.
Previous studies had identified one resistance mechanism caused by the production of pentapeptide repeat proteins (PRPs), a family of molecules that also act as DNA gyrase inhibitors.
One of these, called MfpA, confers quinolone resistance to Mycobacterium tuberculosis, the causative agent of TB.

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In this study John Innes Centre researchers in the group of Professor Tony Maxwell set out to discover how PRPs such as MfpA, work at the molecular level.
They purified MfpA from Mycobacterium smegmatis, a close relative of M. tuberculosis, and showed that it can inhibit the supercoiling reaction of DNA gyrase, the target of quinolones in TB causing mycobacteria.
Further investigations showed that MfpA can prevent poisoning of gyrase by quinolones, thus protecting the bacterial host cell from the antibiotic.
Using X-ray crystallography, the researchers showed that MfpA binds to the ATPase domain of gyrase, and that this explains its ability to both inhibit the supercoiling reaction and prevent quinolone poisoning.
“We did not expect the exact mechanism of MfpA to be the prevention of DNA binding to the gyrase ATPase domain; this is a unique mode of action,” said Professor Tony Maxwell, corresponding author of the study.
“We believe this understanding will help drive new ideas for antibiotic development among academics and researchers in the pharma industry,” he added.
Further investigative work will involve molecular modelling based on the MfpA-gyrase structure to design small molecules that could mimic this interaction and offer more insights into how it works.

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When a coastline undergoes massive erosion, like a hurricane flattening a beach and its nearby environments, it has to rebuild itself — relying on the resilience of its natural coastal structures to begin piecing itself back together in a way that will allow it to survive the next large phenomena that comes its way.
Drs. Orencio Duran Vinent, assistant professor, and Ignacio Rodriguez-Iturbe, Distinguished University Professor and Wofford Cain Chair I Professor, in the Department of Ocean Engineering at Texas A&M University, are investigating the resilience of barrier islands and coastal dunes after high-water events and storms. In doing so, they are helping engineers and researchers assess the vulnerability of coastal landscapes.
Their full findings were published as related articles in the Proceedings of the National Academy of Sciences titled “Probabilistic structure of events controlling the after-storm recovery of coastal dunes” and “Stochastic dynamics of barrier island elevation.”
“If you understand how dunes grow, then you can take action, for example, in terms of vegetation or artificial barriers, to protect the coastline,” Rodriguez-Iturbe said. “But you cannot protect or manage, in this case, dunes and barrier islands if you don’t first understand the dynamics taking place.”
In general, there are two types of high-water events along the coast: natural disasters like hurricanes and tsunamis, which cause waves that devastate the shoreline, and lesser storm surges, which do not cause widescale damage but still affect the coastal environment. As Duran Vinent explained, it is these smaller, routine events that control the post-storm resiliency of dunes and barrier islands that play a key role in protecting coastal communities by absorbing some of the impact from surges.
“Those events are not really strong enough to erode a mature dune completely, but they are strong enough to prevent one from growing in the first place after a storm that erodes the dunes and the vegetation ecosystem,” he said.

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With that in mind, the research team first studied the structure and properties of such smaller high-water events from around the world, utilizing buoy and other data to calculate characteristics like beach elevation, wave runup and water level to analyze them.
Their findings were twofold: first, they confirmed that the high-water events happen randomly and unrelatedly to one another. Then the team discovered that high-water events around the world shared the same general characteristics and had the same typical frequency per year with a given intensity when measured at beach level.
“This means that we can actually say something about the typical size of these nuisance flooding events or the typical size and frequency of events affecting the recovery of the coastal environment,” Duran Vinent said. “Regardless of location, we have a unified description. And this simplifies the work for policymakers or managers a lot because then they don’t need complex calculations.”
The team took their newly discovered information and applied it to developing a model that would determine the elevation of a barrier island and, ultimately, whether or not a dune would be able to succeed. Additionally, this model provides a valuable tool in rebuilding coastlines that have been broken down and deteriorated over time, as it gives engineers a way to see how tall a dune or barrier island needs to be in order to prevent frequent overwashes and, thus, ensure ecosystem survival.
“The dynamic between high-water events and the geomorphology of barrier islands is complicated because the impact of any high-water event depends on how big the dunes are,” Rodriguez-Iturbe said.
“And then while the dune is growing, you have these high-water events randomly interrupting its growth,” Duran Vinent said. “This means that there is a competition between the frequency of the high-water erosional event and how fast the dune is growing.”
This competition became the base of their analytical equation developed to determine whether or not a dune would be able to succeed, mathematically mapping in which conditions a barrier island would be resilient or vulnerable.
Dunes on barrier islands are vitally important, Duran Vinent explained, because they prevent water events from breaching the island and protect the vegetation on the back of the island from flooding, allowing a diverse set of vegetation to grow that is otherwise intolerant to seawater.
The research team also included ocean engineering graduate students Tobia Rinaldo and Kiran Adhithya Ramakrishnan, as well as collaboration with Dr. Benjamin E. Schaffer, research associate at Princeton University.

A study led by UT Southwestern and Children’s Health researchers defines parameters for the number of white blood cells that must be present in children’s urine at different concentrations to suggest a urinary tract infection (UTI). The findings, published recently in Pediatrics, could help speed treatment of this common condition and prevent potentially lifelong complications.
UTIs account for up to 7 percent of fevers in children up to 24 months old and are a common driver of hospital emergency room visits. However, says study leader Shahid Nadeem, M.D., assistant professor of pediatrics at UTSW as well as an emergency department physician and pediatric nephrologist at Children’s Medical Center Dallas, these bacterial infections in infants and toddlers can be difficult to diagnose because their symptoms are similar to other fever-causing conditions.
If a diagnosis is delayed, he explains, a UTI can develop into a serious infection that can cause lasting consequences. For example, UTI-related kidney scarring has been linked with hypertension and chronic kidney disease later in life.
To diagnose a UTI, doctors must culture a urine sample and wait for it to grow telltale bacteria in a petri dish containing nutrients. However, says Nadeem, this process can take up to two days, delaying treatment. Consequently, he and other doctors typically rely on testing urine for a white blood cell-linked protein known as leukocyte esterase (LE), then confirm the presence of white blood cells — a sign of immune activity — by looking for them in urine under a microscope.
In children, he adds, the number of white blood cells can be highly variable, with some of this variation potentially due to varying urine concentration. As such, it’s been unknown what white blood cell number threshold should be used to begin treating a suspected UTI based on urine concentration.
To determine these parameters, Nadeem and his colleagues searched medical records of children younger than 24 months old who were brought to the emergency department at Children’s Medical Center between January 2012 and December 2017 with a suspected UTI and had both a urinalysis — in which their urine concentration and the presence of LE and white blood cells were assessed — and a urine culture. The search turned up 24,171 patients, 2,003 of whom were diagnosed with a UTI based on urine culture.
Using their urine’s specific gravity — the density of urine compared with water, a measurement that serves as a surrogate for concentration — and the number of white blood cells present in the field of a high-power microscope, the researchers came up with cutoff points for three urine concentration groups: For low urine concentrations, children needed only three white blood cells to suspect UTI; for moderate concentrations, that number was six; and for high concentrations, it was eight.
For each of these concentration groups, leukocyte esterase remained constant, says Nadeem — suggesting that it’s a good trigger for analyzing urine for the presence of white blood cells.
Knowing how many white blood cells tend to be present in urine samples at different concentrations in children with UTIs could help physicians start treating these infections before they receive urine culture results, he adds, giving relief to patients and their parents and preventing complications.
“The earlier we can start treatment, the better it is for these young patients,” Nadeem says. “Our results add more information to physicians’ toolboxes to make this decision.”
Other UTSW/Children’s Health researchers who contributed to this study include Mohamed Badawy, Oluwaseun Oke, Laura M. Filkins, Jason Y. Park, and Halim M. Hennes.

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A new study of the U.K. and South Africa variants of SARS-CoV-2 predicts that current vaccines and certain monoclonal antibodies may be less effective at neutralizing these variants and that the new variants raise the specter that reinfections could be more likely.
The study was published in Nature on March 8, 2021. A preprint of the study was first posted to BioRxiv on January 26, 2021.
The study’s predictions are now being borne out with the first reported results of the Novavax vaccine, says the study’s lead author David Ho, MD. The company reported on Jan. 28 that the vaccine was nearly 90% effective in the company’s U.K. trial, but only 49.4% effective in its South Africa trial, where most cases of COVID-19 are caused by the B.1.351 variant.
“Our study and the new clinical trial data show that the virus is traveling in a direction that is causing it to escape from our current vaccines and therapies that are directed against the viral spike,” says Ho, the director of the Aaron Diamond AIDS Research Center and the Clyde’56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.
“If the rampant spread of the virus continues and more critical mutations accumulate, then we may be condemned to chasing after the evolving SARS-CoV-2 continually, as we have long done for influenza virus,” Ho says. “Such considerations require that we stop virus transmission as quickly as is feasible, by redoubling our mitigation measures and by expediting vaccine rollout.”
After vaccination, the immune system responds and makes antibodies that can neutralize the virus.

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Ho and his team found that antibodies in blood samples taken from people inoculated with the Moderna or Pfizer vaccine were less effective at neutralizing the two variants, B.1.1.7, which emerged last September in England, and B.1.351, which emerged from South Africa in late 2020. Against the U.K. variant, neutralization dropped by roughly 2-fold, but against the South Africa variant, neutralization dropped by 6.5- to 8.5-fold.
“The approximately 2-fold loss of neutralizing activity against the U.K. variant is unlikely to have an adverse impact due to the large ‘cushion’ of residual neutralizing antibody activity,” Ho says, “and we see that reflected in the Novavax results where the vaccine was 85.6% effective against the U.K. variant.”
Data from Ho’s study about the loss in neutralizing activity against the South Africa variant are more worrisome.
“The drop in neutralizing activity against the South Africa variant is appreciable, and we’re now seeing, based on the Novavax results, that this is causing a reduction in protective efficacy,” Ho says.
The new study did not examine the more recent variant found in Brazil (B.1.1.28) but given the similar spike mutations between the Brazil and South Africa variants, Ho says the Brazil variant should behave similarly to the South Africa variant.

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“We have to stop the virus from replicating and that means rolling out vaccine faster and sticking to our mitigation measures like masking and physical distancing. Stopping the spread of the virus will stop the development of further mutations,” Ho says.
The study also found that certain monoclonal antibodies used now to treat COVID patients may not work against the South Africa variant. And based on results with plasma from COVID patients who were infected earlier in the pandemic, the B.1.351 variant from South Africa has the potential to cause reinfection.
New study contains comprehensive analysis of variants
The new study conducted an extensive analysis of mutations in the two SARS-CoV-2 variants compared to other recent studies, which have reported similar findings.
The new study examined all mutations in the spike protein of the two variants. (Vaccines and monoclonal antibody treatments work by recognizing the SARS-CoV-2 spike protein.)
The researchers created SARS-CoV-2 pseudoviruses (viruses that produce the coronavirus spike protein but cannot cause infection) with the eight mutations found in the U.K. variant and the nine mutations found in the South African variant.
They then measured the sensitivity of these pseudoviruses to monoclonal antibodies developed to treat COVID patients, convalescent serum from patients who were infected earlier in the pandemic, and serum from patients who have been vaccinated with the Moderna or Pfizer vaccine.
Implications for monoclonal antibody treatments
The study measured the neutralizing activity of 18 different monoclonal antibodies — including the antibodies in two products authorized for use in the United States.
Against the U.K. variant, most antibodies were still potent, although the neutralizing activity of two antibodies in development was modestly impaired.
Against the South Africa variant, however, the neutralizing activity of four antibodies was completely or markedly abolished. Those antibodies include bamlanivimab (LY-CoV555, approved for use in the United States) that was completely inactive against the South Africa variant, and casirivimab, one of the two antibodies in an approved antibody cocktail (REGN-COV) that was 58-fold less effective at neutralizing the South Africa variant compared to the original virus. The second antibody in the cocktail, imdevimab, retained its neutralizing ability, as did the complete cocktail.
“Decisions of the use of these treatments will depend heavily on the local prevalence of the South Africa and Brazil variants,” Ho says, “highlighting the importance of viral genomic surveillance and proactive development of next-generation antibody therapeutics.”
Reinfection implications
Serum from most patients who had recovered from COVID earlier in the pandemic had 11-fold less neutralizing activity against the South Africa variant and 4-fold less neutralizing activity against the U.K. variant.
“The concern here is that reinfection might be more likely if one is confronted with these variants, particularly the South Africa one,” Ho says.

An analysis of several large studies involving participants from more than 60 countries, spearheaded by researchers from McMaster University, has found that eating oily fish regularly can help prevent cardiovascular disease (CVD) in high-risk individuals, such as those who already have heart disease or stroke.
The critical ingredient is omega-3 fatty acids, which researchers found was associated with a lower risk of major CVD events such as heart attacks and strokes by about a sixth in high-risk people who ate two servings of fish rich in omega-3 each week.
“There is a significant protective benefit of fish consumption in people with cardiovascular disease,” said lead co-author Andrew Mente, associate professor of research methods, evidence, and impact at McMaster and a principal investigator at the Population Health Research Institute.
No benefit was observed with consumption of fish in those without heart disease or stroke.
“This study has important implications for guidelines on fish intake globally. It indicates that increasing fish consumption and particularly oily fish in vascular patients may produce a modest cardiovascular benefit.”
Mente said people at low risk for cardiovascular disease can still enjoy modest protection from CVD by eating fish rich in omega-3, but the health benefits were less pronounced than those high-risk individuals.
The study was published in JAMA Internal Medicine on March 8.
The findings were based on data from nearly 192,000 people in four studies, including about 52,000 with CVD, and is the only study conducted on all five continents. Previous studies focused mainly on North America, Europe, China and Japan, with little information from other regions.
“This is by far the most diverse study of fish intake and health outcomes in the world and the only one with sufficient numbers with representation from high, middle and low income countries from all inhabited continents of the world,” said study co-lead Dr. Salim Yusuf, professor of medicine at the Michael G. DeGroote School of Medicine and executive director of the PHRI.
This analysis is based in data from several studies conducted by the PHRI over the last 25 years. These studies were funded by the Canadian Institutes for Health Research, several different pharmaceutical companies, charities, the Population Health Research Institute and the Hamilton Health Sciences Research Institute.

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