Противосудорожный препарат ламотригин может дать начало новому классу антибиотиков — ингибиторам сборки бактериальных рибосом

В связи с растущей проблемой антибиотикорезистентнтности активно ведутся поиски новых антибактериальных препаратов, действующих как уже на известные «мишени», так на структуры бактериальной клетки, ранее не являвшиеся мишенью действия антибиотиков. Причём если ранее в основном пытались ингибировать важнейшие процессы жизнедеятельности микроорганизмов, то сейчас рассматриваются и варианты воздействия на построение (сборку) отдельных структур микробной клетки.

Исследователями был проведён скрининг большого числа уже применяющихся в клинической практике лекарственных средств на наличие зависимой от температуры способности ингибировать рост Escherichia coli. Одним из препаратов, активность которого наиболее выраженно уменьшалась при снижении температуры, был давно применяющийся противосудорожный препарат ламотригин. В присутствии ламотригина в микробных клетках быстро возрастала концентрация незрелых 30S и 50S субъединиц рибосом. При этом препарат не нарушал процесс трансляции и непосредственно не влиял на синтез белков in vitro и in vivo. Таким образом, ламотригин может стать первым представителем целого нового класса антибактериальных препаратов — ингибиторов сборки бактериальных рибосом.

Однако, несмотря на очевидную перспективность разработки антибиотиков с новыми механизмами действия, вероятность развития к ним устойчивости также возможна. В частности, ряд спонтанных мутаций в домене II фактора инициации трансляции IF2 блокируют присоединение ламотригина к IF2 и, соответственно, нивелируют активность данного препарата в отношении процесса сборки бактериальных рибосом.

 Противосудорожный препарат ламотригин может дать начало новому классу антибиотиков — ингибиторам сборки бактериальных рибосом

Механизм неврологических побочных эффектов сульфаниламидов

The team drew from previous research showing that blocking the activity of a certain enzyme (sepiapterin reductase) affects the levels of an important molecule called tetrahydrobiopterin (BH4) in cells. BH4 is critical for the production of neurotransmitters like serotonin and dopamine, and BH4 deficiency causes similar neurological problems to those associated with sulfonamide side effects. 

The EPFL scientists showed for the first time that sulfonamides actually bind to the part of the enzyme that makes BH4. Using a high-throughput drug screening system, the researchers identified ten sulfonamides that strongly inhibit the enzyme. Taking advantage of the expertise of Florence Pojer at EPFL's Global Health Institute, the scientists were able to solve the enzyme's molecular structure and determine how sulfonamides bind to it.

 New Understanding Of The Neurological Side Effects Of Sulfonamide Antibiotics

РКИ миноциклина

The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy, emotional blunting, and social withdrawal. Such ‘negative’ symptoms are unaffected by current antipsychotic therapies. There is evidence that the antibiotic minocycline has neuroprotective properties. We investigated whether the addition of minocycline to treatment as usual (TAU) for 1 year in early psychosis would reduce negative symptoms compared with placebo. In total, 144 participants within 5 years of first onset in Brazil and Pakistan were randomised to receive TAU plus placebo or minocycline. The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale. Some 94 patients completed the trial. The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7, an adjusted difference of 3.53 (s.e. 1.01) 95% CI: 1.55, 5.51; p < 0.001 in the intention-to-treat population. The effect was present in both countries. The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation.

Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment

Исследования миноциклина при шизофрении

A cheap antibiotic normally prescribed to teenagers for acne is to be tested as a treatment to alleviate the symptoms of psychosis in patients with schizophrenia, in a trial that could advance scientific understanding of the causes of mental illness.
The National Institute for Health Research is funding a £1.9m trial of minocycline, which will begin recruiting patients in the UK next month. The research follows case reports from Japan in which the drug was prescribed to patients with schizophrenia who had infections and led to dramatic improvements in their psychotic symptoms.
The chance observation caused researchers to test the drug in patients with schizophrenia around the world. Trials in Israel, Pakistan and Brazil have shown significant improvement in patients treated with the drug.
Scientists believe that schizophrenia and other mental illnesses including depression and Alzheimer's disease may result from inflammatory processes in the brain. Minocycline has anti-inflammatory and neuroprotective effects which they believe could account for the positive findings.

Scientists shocked to find antibiotics alleviate symptoms of schizophrenia

Антидепрессивная активность клавулановой кислоты не подтвердилась

The randomized, double-blind, placebo-controlled study compared two doses of Serdaxin, 0.5 mg and 5 mg, to placebo over an 8-week treatment period. Results from the study did not demonstrate Serdaxin's efficacy compared to placebo measured by the Montgomery-Asberg Depression Rating Scale (MADRS).

Rexahn Pharmaceuticals Announces Phase II Results for Serdaxin as Treatment for Major Depressive Disorder

Циклосерин и аутизм

Researchers have launched a pilot clinical trial of a new medication aimed at relieving the sociability problems of adolescent and young adult patients with autism spectrum disorders (ASD).

The medication used, D-Cycloserine, originally was developed to treat tuberculosis, but previous studies showed, by chance, that it might change social behavior.

New Drug May Ease Social Impairment of Autism