Indian researchers reverse multidrug resistance in E. coli

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(From left) Dr. Saurabh Mishra, Dr. Amit Singh and Prashant Shukla of IISc have been able to make drug-resistant E. coli become sensitive to antibiotics by inhibiting hydrogen sulphide synthesis.

Indian researchers have unravelled the mechanism by which hydrogen sulphide (H2S) gas produced by bacteria protects them from antibiotics and plays a key role in helping bacteria develop drug resistance. And by blocking/disabling the enzyme that triggers the biosynthesis of hydrogen sulphide in bacteria, the researchers from Bengaluru’s Indian Institute of Science (IISc) and Indian Institute of Science Education and Research (IISER) Pune have been able to reverse antibiotic resistance in E. coli bacteria; E. coli bacteria were isolated from patients suffering from urinary tract infection. The results were published in the journal Chemical Science.

Antibiotics kill by increasing the levels of reactive oxygen species (oxidative stress) inside bacterial cells. So any mechanism that detoxifies or counters reactive oxygen species generated by antibiotics will reduce the efficacy of antibiotics. “Hydrogen sulphide does this to nullify the effect of antibiotics,” says Dr. Amit Singh from the Department of Microbiology and Cell Biology at IISc and one of the corresponding authors of the paper. “When bacteria face reactive oxygen species a protective mechanism in the bacteria kicks in and more hydrogen sulphide is produced.” Hydrogen sulphide successfully counters reactive oxygen species and reduces the efficacy of antibiotics.

There was nearly 50% reduction in drug-resistance when hydrogen sulphide production was blocked.The researchers carried out simple experiments to establish this. They first ascertained that regardless of the mode of action of antibiotics, the drugs uniformly induce reactive oxygen species formation inside E. coli bacteria. Then to test if increased levels of hydrogen sulphide gas inside bacteria counter reactive oxygen species produced upon treatment with antibiotics, a small molecule that produces hydrogen sulphide in a controlled manner inside the bacteria was used. “Hydrogen sulphide  released by the molecule was able to counter reactive oxygen species and reduce the ability of antibiotics to kill bacteria,” says Dr. Singh.

Harinath-Optimized

Prof. Harinath Chakrapani’s team at IISER Pune synthesised the small molecule.

The small molecule was synthesised by a team led by Prof. Harinath Chakrapani from the Department of Chemistry, IISER, Pune; he is one of the corresponding authors of the paper. “We designed the small molecule keeping in mind that synthesis should be easy, efficiency in producing hydrogen sulfide should be high and the molecule should release hydrogen sulfide only inside bacteria and not mammalian cells,” says Vinayak S. Khodade from the Department of Chemistry, IISER, Pune and one of the authors of the paper who contributed equally like the first author. The researchers were able to selectively increase hydrogen sulphide levels inside a wide variety of bacteria.

To reconfirm hydrogen sulphide’s role in countering reactive oxygen species, the team took multidrug-resistant, pathogenic strains of E. coli from patients suffering from urinary tract infection and measured the hydrogen sulphide levels in these strains. “We found the drug-resistant strains were naturally producing more hydrogen sulphide compared with drug-sensitive E. coli,” says Prashant Shukla from the Department of Microbiology and Cell Biology at IISc and the first author of the paper. So the team used a chemical compound that inhibits an enzyme responsible for hydrogen sulphide production. “There was nearly 50% reduction in drug-resistance when hydrogen sulphide production was blocked,” Dr. Singh says.

“Bacteria that are genetically resistant to antibiotics actually become sensitive to antibiotics when hydrogen sulphide synthesis is inhibited,” says Prof. Chakrapani. The multidrug-resistant E. coli regained its ability to survive antibiotics when hydrogen sulphide was once again supplied by introducing the small molecule synthesised by Prof. Chakrapani.

“As a result of our study, we have a found new mechanism to develop a new class of drug candidates that specifically target multidrug-resistant bacteria,” says Prof. Chakrapani. The researchers already have a few inhibitors that seem capable of blocking hydrogen sulfide production. But efforts are on to develop a library of inhibitors to increase the chances of success.

How H2S acts

The researchers identified that E. coli has two modes of respiration involving two different enzymes. The hydrogen sulfide gas produced shuts down E. coli’s aerobic respiration by targeting the main enzyme (cytochrome bo oxidase (CyoA)) responsible for it. E. coli then switches over to an alternative mode of respiration by relying on a different enzyme — cytochrome bd oxidase (Cydb). Besides enabling respiration, the Cydb enzyme detoxifies the reactive oxygen species produced by antibiotics and blunts the action of antibiotics.

“So we found that hydrogen sulfide activates the Cydb enzyme, which, in turn, is responsible for increasing resistance towards antibiotics,” says Dr. Singh. “If we have a drug-like molecule(s) that blocks hydrogen sulfide production and inhibits Cydb enzyme activity then the combination will be highly lethal against multidrug-resistant bacteria.” This combination can also be used along with antibiotics to effectively treat difficult-to-cure bacterial infections.

The link between hydrogen sulfide and Cydb enzyme in the emergence of drug resistance is another key finding of the study.

Published in The Hindu on May 6, 2017

IISc’s potent molecules show promise for TB therapy

SEM photo of Mycobacterium tuberculosis bacteria. - Photo NIAD-Optimized

The two molecules were able to prevent biofilm formation and even disrupt biofilms that had formed.

Scientists at the Indian Institute of Science (IISc) Bengaluru have developed two new, potent molecules that can severely impact the survival of mycobacteria, including Mycobacterium tuberculosis that causes TB. The results were published in the journal Antimicrobial Agents and Chemotherapy.

Unlike most antibiotics that target the bacterial metabolism by aiming at the cellular components, the novel molecules inhibit the stress response pathway of mycobacteria. The stress response pathway is crucial for bacteria to survive during hostile conditions such as lack of nutrients and the presence of antibiotics, to name a few. So any inhibition of this pathway will lead to its death.

The master regulator of stress pathway in the case of mycobacteria is (p)ppGpp (Guanosine pentaphospahte or Guanosine tetraphosphate). Though a molecule that inhibits the (p)ppGpp formation has already been synthesised, the efficacy is not much. “Very high concentration of Relacin molecule is needed to inhibit the pathway and, therefore, the efficacy is low. So we synthesised two new molecules — acetylated compound (AC compound) and acetylated benzoylated compound (AB compound) — by bringing about a modification in the base of the Relacin molecule,” says Prof. Dipankar Chatterji from the Division of Biological Sciences at IISc and the corresponding author of the paper.

“We found both the molecules to be very good inhibitors of stress response. The two compounds affected the rate of synthesis of (p)ppGpp and also reduced the cell survival,” he says. Laboratory studies showed that the two molecules were not toxic to human cells and were able to penetrate the human lung epithelial cells.

IMG_0508

Inhibiting (p)ppGpp synthesis would target the survival of the bacteria, says Dr. Kirtimaan Syal.

“We found our compounds were targeting the Rel gene. The Rel gene makes Rel protein, which in turn synthesises (p)ppGpp. When the Rel gene is knocked out, the long-term survival of Mycobacterium smegmatis decreases,” says Prof. Chatterji.

“The Alarmone molecule “(p)ppgpp”, a modified nucleotide, is ubiquitous in bacteria and absent in humans. Inhibiting (p)ppgpp synthesis would specifically target the survival of bacteria without having any effects on humans,” says Dr. Kirtimaan Syal from the Division of Biological Sciences, IISc and the first author of the paper.

Earlier studies have shown that when the rel gene is deleted, the long-term survival ability under stress was lost; the M. tuberculosis bacteria was unable to persist in mice and unable to form tubercle lesions in guinea pigs.

“The major reason for prolonged treatment of TB is the bacterium’s ability to persist in dormant form, which is tolerant to most antibiotics used in the treatment regimen. So inhibition of (p)ppGpp-mediated persistence could help in shortening the treatment regime, dealing with the emergence of multiple drug resistance and treatment of chronic infections, Dr. Syal says.

Inhibiting biofilm

Under hostile conditions, bacteria tend to form biofilms, which protect the bacteria from stress and induce tolerance to antibiotics. Recent studies have shown that tuberculosis bacteria that cannot form a biofilm cannot survive inside the host. Evidences have shown that at the time of infection, the M. tuberculosis display a biofilm-like phenotype and this helps the bacteria to survive inside the host.

Studies carried out by the researchers showed that both the molecules were able to inhibit biofilm formation by M. tuberculosis and M. smegmatis and also disrupt the already formed biofilm. “The biofilm formed by TB bacteria is very dangerous. The ability of the molecules to destroy the biofilm and even prevent its formation is a very important achievement,” says Prof. Chatterji.

Since there are very few antibiotics that target the stress response pathway of the bacteria, the two molecules offer great promise. “The next step is to test the molecules on animals. We have not thought about it. It will also be interesting to see if the bacteria develop resistance against these molecules,” Prof. Chatterji says.

Published in The Hindu on April 15, 2017

Why is TB bacteria not on WHO’s deadly superbug list?

Pharmacy - Photo R. PrasadOf the estimated 10.4 million new tuberculosis cases globally in 2015, nearly 0.5 million estimated cases were multidrug-resistant (MDR) TB cases. Another nearly one million were resistant to rifampicin drug alone. India accounted for 2.84 million new cases in 2015, of which 79,000 had MDR-TB. There were 1.4 million TB deaths worldwide in 2015.

For the first time in nearly 50 years, two new drugs, bedaquiline and delamanid, were approved by the US Food and Drug Administration for use in MDR-TB cases. The accelerated approval of bedaquiline by the FDA was based on interim Phase IIa data. The lack of large-scale safety data and the paucity of effective TB drugs, especially for MDR-TB, are the reasons why the World Health Organisation insists that the drug be used only when all “options to treat TB using existing drugs have been exhausted”. The WHO also makes it abundantly clear that all efforts should be taken to avoid TB bacteria from developing drug resistance to bedaquiline as a result of misuse.

Despite the gravity of the situation and a near-empty drug chest to fight TB in India, a WHO list, released on February 27 of drug-resistant bacteria that pose the “greatest threat to human health” and for which new drugs are desperately needed, has no mention of Mycobacterium tuberculosis, the bacteria which causes TB.

Not a priority pathogen?
This is the first time that the WHO has released such a list and the prime objective of listing the “priority pathogens”, in its own words, is to “guide and promote research and development of new antibiotics… and to address the growing global resistance to antimicrobial medicines”.

The list is divided into three categories — critical, high and medium —based on the urgency of need for new drugs. While the WHO reasons that malaria and HIV have not been included in the list as they are not bacterial infections, it cites a completely different reason for not including TB bacteria. According to the WHO, TB bacterium was not included in the list as it is already targeted by other “dedicated programmes”.

In a strongly worded open letter to WHO’s Director-General Dr Margaret Chan, The International Union Against Tuberculosis and Lung Diseases, or simply The Union, says it is “outrageous” that Mycobacterium tuberculosis was not considered for inclusion as it is “already a globally established priority for which innovative new treatments are urgently needed”.

“This explanation defies reason [and] contradicts the stated intent of the global priority pathogens list’s methodology to define the list,” the letter reads. “TB’s exclusion sends the false and counterproductive message that drug-resistant TB is not an urgent public health threat,” the letter says. It also send a strong message to policymakers to “deprioritise TB research”, it adds.

Meets criteria for inclusion
The reason why The Union has reacted so strongly is because the TB bacteria meets each of the 10 criteria used for inclusion in the list — how deadly the infections are, the number of infected people in a community, prevalence of resistance, how easily the bacterium spreads from one person to another, options to prevent the infection in hospital and community, treatment options and whether new drugs are already in the R&D pipeline.

The WHO states that new antibiotics most urgently needed will never be developed in time if it is left to market forces alone. This is best demonstrated in the case of TB. It took nearly 50 years for new TB drugs to be approved for MDR-TB and not a single antibiotic has been developed for drug-sensitive TB in half a century.

Since the WHO has stated that the list has been developed to allow periodic revisions and inclusions of other pathogens, including viruses and parasites, The Union wants the TB bacteria to be included in the list before the WHO publishes the full protocol and results by the end of May 2017.

Published in The Hindu on March 5, 2017

IISc produces a novel salt to better combat bacterial infections

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The salt developed by Dr. Shanmukha Prasad Gopi (left) and Prof. Gautam Desiraju (right) of IISc is highly efficacious than a physical mixture of the two drugs.

Using crystal engineering, a team of researchers from the Indian Institute of Science (IISc) Bangalore has successfully produced a highly efficacious binary salt of two commonly used drugs — norfloxacin (antibacterial) and sulfathiazole (antimicrobial). The salt is more effective than a physical mixture of the two drugs. The results were published in the journal Molecular Pharmaceutics.

Better solubility

The two drugs were ground for nearly 30 minutes and made into a solution from which the salt was produced. It has enhanced pharmaceutical effects compared to the physical mixture of the two drugs.

The underlying reason for the salt’s improved efficacy is the better solubility and diffusion of the drugs, particularly norfloxacin and, therefore, enhanced bioavailability and pharmaceutical activity.

“Norfloxacin in a pure form or in a physical mixture has low solubility and permeability, so the amount of the drug that goes through the membrane and gets into tissues is less. To compensate for this, higher dosages of norfloxacin drug are generally used,” says Prof. Gautam R. Desiraju from the Solid State and Structural Chemistry Unit at IISc and the corresponding author of the paper.

The salt has properties that are more than the aggregate of the individual drug properties.But in the case of the binary salt, a “large enhancement in overall solubility” was seen at pH 7.4, which is generally seen in the small intestine where most of the absorption takes place. Most importantly, both the drugs showed comparable solubility when present in the salt form.

Similarly, in the case of permeability, the amount of binary salt diffusing through the membrane was much higher in the first hour. In contrast, the parent drugs show much lower diffusion. When the drugs are present together in a physical mixture, each one has a different rate of diffusion across the membrane. “But in the case of the binary salt both diffuse together. It is like sulfathiazole pulls norfloxacin across the membrane so both the drugs are available at the same time at the site of action to combat the microbes together,” he says.

“We are trying to study the mechanism behind the increased diffusion so that we have molecular level understanding of what precisely is happening,” Prof. Desiraju says.

“Generally the salt form increases solubility and because of high solubility or concentration gradient diffusion gets enhanced,” says Dr. Shanmukha Prasad Gopi from IISc and the first author of the paper.

Potency tested

The potency of the salt and the physical mixture of the drugs was tested on E. coli, Staphylococcus aureus and fungi. Studies showed that the salt was able to achieve the same result of inhibiting bacterial and fungal growth at about half the concentration of the physical mixture.

For the same dosage, the salt had nearly five times greater area that was clear of microbes than the physical mixture of the two drugs. The greater inhibition of microbes around the salt might be due to greater solubility and faster release of norfloxacin from the salt compared with the pure form and the simultaneous presence of both the drugs at the site of action when present as a salt. “The salt has properties that are more than the aggregate of the individual properties,” Prof. Desiraju says.

Due to enhanced solubility, the amount of norfloxacin required will be less and, therefore, lesser chances of developing resistance against the drug. The team has patented the salt. A Mumbai-based pharmaceutical company has already shown interest in the salt.

Published in The Hindu on November 3, 2016

IIT Hyderabad finds a chink in E. coli armour

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The IIT Hyderabad team led by Dr. Thenmalarchelvi Rathinavelan is look at different strategies to make E. coli vulnerable to attack by the host’s immune system.

Researchers at the Indian Institute of Technology, Hyderabad (IIT-H) have made a promising start to render E. coli  bacteria more susceptible to host immune response. The researchers have found a potential way of preventing the bacterial surface-associated polysaccharide — capsular polysaccharide (CPS) or K antigen — from attaching on the surface membrane and forming a protective encapsulation of the bacteria, thus making the E. coli  vulnerable to attack by the host’s immune system.

The CPS is synthesised by the bacteria and exported to the surface to offer protection by evading the host immune response. Surface-association of CPS also offers impermeability to antibiotics, thus establishing infection in the host. Certain surface-associated bacterial proteins help in the attachment of CPS on the bacterial surface.

“If you know how the CPS is attached to the bacteria’s membrane protein then we can design a drug that can go and bind to the protein and prevent the CPS from getting attached to the bacterial surface,” says Dr. Thenmalarchelvi Rathinavelan from the Department of Biotechnology, IIT Hyderabad.

optimal concentration of CPS should be maintained, and this is achieved through water conduction.“The CPS is not the same in all the E. coli strains but varies. In all, there are 80 such capsular polysaccharides. We have modelled the 3D structures and developed an organised repository of 72 CPS varieties,” says Dr. Rathinavelan the corresponding author of a paper published in the journal Nucleic Acids Research. “The database is called EK3D [E. coli K antigen 3-Dimensional Structure Database].” The database can facilitate the development of efficacious drugs against E. coli infections.

After developing the models of 72 CPS structures, the team led by Dr. Rathinavelan has proposed the binding site of CPS on the membrane protein surface. The results were published in June 2016 in the journal Scientific Reports.

Dual role

“The bacterial membrane protein has a dual role. Besides facilitating the binding of CPS, it also conducts water from inside the bacteria to outside and from outside to inside to maintain the osmotic pressure,” she says. The team has identified five water diffusion points (two inside and three outside the bacteria).

The osmotic pressure becomes high when the amount of CPS is more on the surface. Under such circumstances, water is transported from inside the bacteria to outside to dilute and spread the concentration of CPS and avoid the rupturing of the cell. This also helps in keeping the CPS in a hydrated condition and prevents further accumulation of CPS on the surface. But when the concentration of CPS is less on the surface the pressure inside the bacteria reduces. Water is transported from outside to inside the bacteria to normalise the pressure.

“Basically, optimal concentration of CPS should be maintained, and this is achieved through water conduction, called osmoregulation,” Dr. Rathinavelan says.

The team is now working on proving what they had observed — the attachment region of CPS to the membrane protein and the dual role of the protein in conducting water.

“If we can alter the water conduction property of the protein we can control the accumulation of CPS on bacterial surface and make the bacteria accessible to the host immune system,” she says. “Alternatively, if we block the CPS binding site with a drug molecule then CPS cannot bind to the bacterial membrane. The site where the protein binds to the membrane can also be targeted. These strategies may pave the way for tackling emergence of multi-drug resistance in Gram-negative bacteria.”

Published in The Hindu on October 9, 2016

Pharmacies in India may not be causing TB drug-resistance

Pharmacy - Photo R. Prasad

Thirty-seven per cent of 622 pharmacies in Mumbai, Delhi and Patna handed out antibiotics to TB ‘patients’ with symptoms. – Photo: R. Prasad

If an earlier study revealed the tendency of private practitioners to liberally use antibiotics to treat tuberculosis leading to a delay in TB diagnosis and treatment and increase the chances of TB spreading within a community, pharmacies in Delhi, Mumbai and Patna are no better. A study published on August 25, 2016 in the journal The Lancet found that a majority of 622 pharmacies in the three cities dispensed antibiotics to TB patients even when they did not carry a prescription.

According to government guidelines, “pharmacies are required to counsel patients with TB, identify and refer persons with tuberculosis symptoms to the nearest public health facilities for testing” and dispense TB drugs. Much like the private practitioners, pharmacies tend to be the first point of contact for primary care in India.

Srinath Satyanarayana, the first author of the paper from McGill University, Montreal, Canada used standardised TB patients — healthy individuals trained to pose as TB patients and interact with pharmacists — to understand how pharmacies in the three cities treated patients presenting with TB symptoms or microbiological confirmation of pulmonary TB. The other main objective was to determine whether the pharmacies were contributing to the inappropriate use of antibiotics.

The standardised patient 1 presented with 2-3 weeks of cough and fever and was directly seeking drugs from a pharmacy. The standardised patient 2 presented with one month of cough and microbiological confirmation of TB from a sputum test.

Only 13 per cent of simulated patients with TB symptoms and 62 per cent of patients with microbiological confirmation were correctly managed.As expected, liberal dispensation of antibiotics was seen in the case of standardised patient 1. Only 96 of 599 pharmacies (16 per cent) refereed such patients to health-care providers. But ideal case management was in only 13 per cent of the cases as a few pharmacies handed out antibiotics to the patients even while referring them to a physician. Antibiotics (37 per cent), steroids (8 per cent) and fluoroquinolones (10 per cent) were given to standardised patients with symptoms.

“That nearly 37 per cent of the pharmacies are handing our antibiotic to persons presenting with TB symptoms is really worrisome,” says Dr. Satyanarayana in an email to me. But more worrying is the dispensation of fluoroquinolones. “Fluoroquinolones are an essential part of MDR-TB treatment regimen and emerging regimens, so quinolone abuse is a concern,” they write.

In stark contrast, in the case of standardised patient 2 who had a microbiological confirmation of TB disease 67 per cent (401 of 601) of pharmacies referred the patient to a health-care provider.  Like in the earlier case, ideal case management was seen in only 62 per cent as the standardised patient did receive antibiotics (16 per cent) or steroids (3 per cent) even while being referred to a health-care provider.

“In case of TB patients with microbiological confirmation of TB disease, antibiotics (without anti-TB properties) will be ineffective and un-necessary, and can delay the initiation of proper therapy for patients. These patients will continue to spread the disease in the community and TB disease will continue to progress in the concerned individual. Steroids reduce body immunity, suppress symptoms temporarily and can worsen the TB disease,” Dr. Satyanarayana says.

Silver lining

The only silver lining is that none of the pharmacies in all the three cities handed out first-line anti-TB drugs to these “patients.” So pharmacies are unlikely sources of irrational drug use that contributes to multidrug-resistant tuberculosis. “Also, pharmacies are not trying out high end antibiotics such as fluoroquinolones when they realise that the patient has some underlying illness such as TB,” he says.

“TB Drug resistance occurs primarily due to incorrect regimens, intake of drugs irregularly or intake of drugs for very short duration of time. From our study, it appears that pharmacies are not playing a role in deciding the anti-TB regimens and are also not dispensing anti-TB drugs over-the-counter, at least in the three cities that we studied. So the drug resistance in India could be due to either patient related factors or provider related factors or due to health system related factors (which has not created a system for all TB patients in country to access quality assured diagnosis and treatment free of cost and seamlessly),” Dr. Satyanarayana says.

One reason why pharmacies did not dispense anti-TB drugs could be because they belong to a more stringent Schedule H1 category of drugs where details of the prescription and name of the doctors and patients have to be documented and the registry has to be retained for two years.

A novel, powerful antibiotic found inside human nose

MRSA - Photo National Institute of Allergy and Infectious Diseases (NIAID)

The novel antibiotic ludunin, found inside human nose, has antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). – Photo: NIAD

A novel antibiotic — lugdunin — produced by a bacterium found inside the human nose has been found to kill the bacterium Staphylococcus aureus, including drug-resistant forms such as the methicillin-resistant S. aureus (MRSA). The study found S. aureus does not develop resistance against the novel antibiotic. The findings could aid the development of new therapies for hard-to-treat bacterial infections. The results were published today (July 28, 2016) in the journal Nature.

The human body is home to an immense variety of microorganisms known collectively as the microbiota. Several bacteria species including Staphylococcus are found inside the human nose and these bacterial species are fewer in number when the pathogenic S. aureus bacterium is present. However, in about 70 per cent of human population, colonisation by S. aureus inside human nose is absent. The reasons for this were not clear.

On screening a collection of nasal Staphylococcus species for antimicrobial activity against S. aureus, a team of scientists led by Andreas Peschel from the University of Tubingen, Germany, found that Staphylococcus lugdunensis bacterial strain had a particularly strong capacity to prevent the growth of S. aureus.

On screening S. lugdunensis mutants, Dr. Peschel and colleagues identified the compound that resisted the growth of S. aureus and called it lugdunin. Lugdunin causes the breakdown of S. aureus.

Peptide antibiotic

The novel compound represents the first known example of a new class of peptide antibiotics.

Nose

The bacteria producing the novel antibiotic reduced the S. aureus colonisation by six times. – Photo: R. Prasad

The lugdunin’s role in inhibiting S. aureus growth was first proved in the lab. To test the efficacy in animals, the researchers infected mice skin with S. aureus and then treated it with the novel antibiotic 24, 30 and 42 hours after infection had set in. Lugdunin was found to completely clear all viable S. aureus from the surface and in the deeper layers of the skin.

Next, lugdunin’s ability to inhibit S. aureus’ growth in the nose was tested using cotton rats. When both S. aureus and S. lugdunensis bacteria were introduced into the cotton rat nose, relatively fewer S. aureus cells were retrieved proving that lugdunin production effectively prevented S. aureus colonisation inside the nose.

The nasal swabs of 187 hospitalised patients were tested for the presence of S. aureus, S. lugdunensis or both. When both the bacterial species were found in a patient’s nose, S. aureus colonisation was nearly six times lower than in those people who had only S. aureus.

The researchers found lugdunin had bacterial activity against many major pathogens, and S. aureus isolates had “pronounced susceptibility” to lugdunin in all nasal and clinical samples. So it may be quite difficult for S. aureus to develop resistance against lugdunin, they say.

Published in The Hindu on July 28, 2016