̽��ֱ�� of Cambridge - British Lung Foundation

Effectiveness of antibiotics significantly reduced when multiple bugs present

jg533 — Sat, 19 Mar 2022 00:01:00 +0000

In the study, published today in ̽��ֱ��ISME Journal, researchers say that even a low level of one type of microbe in the airways can have a profound effect on the way other microbes respond to antibiotics.

̽��ֱ��results highlight the need to consider the interaction between different species of microbe when treating infections with antibiotics - and to adjust dosage accordingly.

“People with chronic infections often have co-infection with several pathogens, but the problem is we don’t take that into account in deciding how much of a particular antibiotic to treat them with. Our results might help explain why, in these people, the antibiotics just don’t work as well as they should,” said Thomas O’Brien, who carried out the research for his PhD in the ̽��ֱ�� of Cambridge’s Department of Biochemistry and is joint first author of the paper.

Chronic bacterial infections such as those in the human airways are very difficult to cure using antibiotics. Although these types of infection are often associated with a single pathogenic species, the infection site is frequently co-colonised by a number of other microbes, most of which are not usually pathogenic in their own right.

Treatment options usually revolve around targeting the pathogen, and take little account of the co-habiting species. However, these treatments often fail to resolve the infection. Until now scientists have had little insight into why this is.

To get their results the team developed a simplified model of the human airways, containing artificial sputum (‘phlegm‘) designed to chemically resemble the real phlegm coughed up during an infection, packed with bacteria.

̽��ֱ��model allowed them to grow a mixture of different microbes, including pathogens, in a stable way for weeks at a time. This is novel, because usually one pathogen will outgrow the others very quickly and spoil the experiment. It enabled the researchers to replicate and study infections with multiple species of microbe, called ‘poly-microbial infections’, in the laboratory.

̽��ֱ��three microbes used in the experiment were the bacteria Pseudomonas aeruginosa and Staphylococcus aureus, and the fungus Candida albicans – a combination commonly present in the airways of people with cystic fibrosis.

̽��ֱ��researchers treated this microbial mix with an antibiotic called colistin, which is very effective in killing Pseudomonas aeruginosa. But when the other pathogens were present alongside Pseudomonas aeruginosa, the antibiotic didn’t work.

“We were surprised to find that an antibiotic that we know should clear an infection of Pseudomonas effectively just didn’t work in our lab model when other bugs were present,” said Wendy Figueroa-Chavez in the ̽��ֱ�� of Cambridge’s Department of Biochemistry, joint first author of the paper.

̽��ֱ��same effect happened when the microbial mix was treated with fusidic acid – an antibiotic that specifically targets Staphylococcus aureus, and with fluconazole - an antibiotic that specifically targets Candida albicans.

̽��ֱ��researchers found that significantly higher doses of each antibiotic were needed to kill bacteria when it was part of poly-microbial infection, compared to when no other pathogens were present.

“All three species-specific antibiotics were less effective against their target when three pathogens were present together,” said Martin Welch, Professor of Microbial Physiology and Metabolism in the ̽��ֱ�� of Cambridge’s Department of Biochemistry and senior author of the paper.

At present antibiotics are usually only laboratory tested against the main pathogen they are designed to target, to determine the lowest effective dose. But when the same dose is used to treat infection in a person it often doesn’t work, and this study helps to explain why. ̽��ֱ��new model system will enable the effectiveness of potential new antibiotics to be tested against a mixture of microbe species together.

Poly-microbial infections are common in the airways of people with cystic fibrosis. Despite treatment with strong doses of antibiotics, these infections often persist long-term. Chronic infections of the airways in people with asthma and chronic obstructive pulmonary disorder (COPD) are also often poly-microbial.

By looking at the genetic code of the Pseudomonas bacteria in their lab-grown mix, the researchers were able to pinpoint specific mutations that give rise to this antibiotic resistance. ̽��ֱ��mutations were found to arise more frequently when other pathogens were also present.

Comparison with the genetic code of 800 samples of Pseudomonas from around the world revealed that these mutations have also occurred in human patients who had been infected with Pseudomonas and treated with colistin.

“ ̽��ֱ��problem is that as soon as you use an antibiotic to treat a microbial infection, the microbe will start to evolve resistance to that antibiotic. That’s what has happened since colistin started to be used in the early 1990’s. This is another reminder of the vital need to find new antibiotics to treat human infections,” said Welch.

This research was funded by the British Lung Foundation, the Cystic Fibrosis Trust, and the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs).

Reference

O’Brien, T et al: ‘Decreased efficacy of antimicrobial agents in a polymicrobial environment.’ ̽��ֱ��ISME Journal, March 2022. DOI: 10.1038/s41396-022-01218-7

A study has found that much higher doses of antibiotics are needed to eliminate a bacterial infection of the airways when other microbes are present. It helps explain why respiratory infections often persist in people with lung diseases such as cystic fibrosis despite treatment.

People with chronic infections often have co-infection with several pathogens, but the problem is we don’t take that into account in deciding how much of a particular antibiotic to treat them with

Thomas O’Brien

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Woman coughing

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Tiny golden bullets could help tackle asbestos-related cancers

cjb250 — Tue, 27 Oct 2020 11:10:12 +0000

In a study published today in journal Small, the researchers demonstrate that once inside the cancer cells, the nanotubes absorb light, causing them to heat up, thereby killing the cells.

More than 2,600 people are diagnosed in the UK each year with mesothelioma, a malignant form of cancer caused by exposure to asbestos. Although the use of asbestos is outlawed in the UK now, the country has the world’s highest levels of mesothelioma because it imported vast amounts of asbestos in the post-war years. ̽��ֱ��global usage of asbestos remains high, particularly in low- and middle-income countries, which means mesothelioma will become a global problem.

“Mesothelioma is one of the ‘hard-to-treat’ cancers, and the best we can offer people with existing treatments is a few months of extra survival,” said Dr Arsalan Azad from the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge. “There’s an important unmet need for new, effective treatments.”

In 2018, the ̽��ֱ�� of Cambridge was awarded £10million from the Engineering and Physical Sciences Research Council to help develop engineering solutions, including nanotech, to find ways to address hard-to-treat cancers.

In a collaboration between the ̽��ֱ�� of Cambridge and ̽��ֱ�� of Leeds, researchers have developed a form of gold nanotubes whose physical properties are ‘tunable’ – in other words, the team can tailor the wall thickness, microstructure, composition, and ability to absorb particular wavelengths of light.

̽��ֱ��researchers added the nanotubes to mesothelioma cells cultured in the lab and found that they were absorbed by the cells, residing close to the nucleus, where the cell’s DNA lies. When the team targeted the cells with a laser, the nanotubes absorbed the light and heated up, killing the mesothelioma cell.

Professor Stefan Marciniak, also from the Cambridge Institute for Medical Research and a Fellow at St Catharine’s College, Cambridge, added: “ ̽��ֱ��mesothelioma cells ‘eat’ the nanotubes, leaving them susceptible when we shine light on them. Laser light is able to penetrate deep into tissue without causing damage to surrounding tissue. It then gets absorbed by the nanotubes, which heat up and, we hope in the future, could be used to cause localised cancer-cell killing.”

̽��ֱ��team will be developing the work further to ensure the nanotubes are targeted to cancer cells with less effect on normal tissue.

̽��ֱ��nanotubes are made in a two-step process. First, solid silver nanorods are created of the desired diameter. Gold is then deposited from solution onto the surface of the silver. As the gold builds-up at the surface, the silver dissolves from the inside to leave a hollow nanotube.

̽��ֱ��approach advanced by the Leeds team allows these nanotubes to be developed at room temperature, which should make their manufacture at scale more feasible.

Professor Stephen Evans from the School of Physics and Astronomy at the ̽��ֱ�� of Leeds said: “Having control over the size and shape of the nanotubes allows us to tune them to absorb light where the tissue is transparent and will allow them to be used for both the imaging and treatment of cancers. ̽��ֱ��next stage will be to load these nanotubes with medicines for enhanced therapies.”

̽��ֱ��research was funded by the British Lung Foundation, Victor Dahdaleh Foundation, National Institute for Health Research Cambridge Biomedical Research Centre, Royal Papworth Hospital NHS Foundation Trust, Alpha1-Foundation, Medical Research Council and the Engineering & Physical Sciences Research Council.

Reference
Ye, S & Azad, AA et al. Exploring High Aspect Ratio Gold Nanotubes as Cytosolic Agents: Structural Engineering and Uptake into Mesothelioma Cells. Small; 25 Oct 2020: DOI: 10.1002/smll.2003793

Gold nanotubes – tiny hollow cylinders one thousandth the width of a human hair – could be used to treat mesothelioma, a type of cancer caused by exposure to asbestos, according to a team of researchers at the Universities of Cambridge and Leeds.

Mesothelioma is one of the ‘hard-to-treat’ cancers, and the best we can offer people with existing treatments is a few months of extra survival. There’s an important unmet need for new, effective treatments

Arsalan Azad

Confocal fluorescence image of gold nanotures (green) in mesothelioma cells

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