NAM

New Antimicrobials

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 Obiettivo del progetto (Objective)

'Antibacterial resistance is spreading globally at an alarming rate and continues to increase. New potent antibacterial agents and therapies are therefore continually needed. In recent years, new antibacterial compounds have mainly been additions to the existing classes of drugs and very few new structures have been developed. Pharmaceutical industry has little interest in developing novel structures due to high investment and low profit expectancy. The derivatives of existing drugs typically raise bacterial resistance much faster than completely new compounds. To overcome the chronic problem of antibiotic resistance, totally new compounds and approaches are required, involving collaboration of researchers from various sectors and disciplines, as well as high societal investments. The NAM project aims to confront these problems by intense collaboration between industry and academia. The project aims at i) discovery of totally new antibacterial compounds from one of the richest untapped natural sources, endophytes, ii) development of totally new approaches based on antimicrobial host defense peptides, iii) research on the mechanisms of action of antimicrobial compounds. Through these objectives novel anti-infective agents can potentially be applied to the battle against bacterial resistance. NAM is a highly multidisciplinary consortium, consisting of groups in biology, chemistry, biophysics, biochemistry, microbiology and biotechnology. It consists of two companies (one SME and a large biotech company), and three university research laboratories in four different countries within the EU.'

Introduzione (Teaser)

New antimicrobial compounds are needed as bacteria become resistant to currently available drugs. Addressing this pressing issue, the 'New antimicrobials' (NAM) project explored new sources and techniques for developing novel antimicrobials and mechanisms behind their actions.

Descrizione progetto (Article)

The NAM project investigated antimicrobial peptides (AMPs), which are produced by all higher organisms, along with the secondary products of internal plant microbes, known as endophytes. Endophytes live inside plants and provide their host with protection against various types of pathogens by producing bioactive compounds. These compounds may prove potentially useful in antibiotic therapy.

Project partners developed techniques for isolating and screening endophytic fungi. They found that the highest level of bioactive fungi that acted against the Staphylococcus aureus bacterium was contained in grasses, spruce and pine respectively.

Endophytic microorganisms cannot be easily cultured in the laboratory, therefore scientists investigated genetic tools that allowed them to access active sources from the inside the plant. They successfully identified one antibacterial protein and several AMPs from endophytes present in crowberry (Empetrum nigrum), northern Labrador tea (Rhododendron tomentosum) and Scots pine (Pinus sylvestris).

Researchers did not only focus on AMPs from endophytic sources but also from other bacteria and fungi, as well as molecules produced as part of animal host defence mechanisms. Many AMPs of animal origin have the capacity to directly inactivate pathogens as well as alert and strengthen the immune system.

Scientists considered different classes of AMPs, concentrating on those that possessed broad spectrum activity directed at the microbial membrane and those with selective activity against Gram-negative bacteria. The different classes included animal cathelicidins and beta-defensins, fungal defensins (plectasin) and bacterial lantibiotics. Cathelicidins are an important family of AMPs present in all vertebrate animals.

A detailed study was carried out into the antibacterial action of beta-defensin 3, which is produced by human epithelial cells and white blood cells called neutrophils and which binds to Lipid II-rich sites, thereby disrupting microbial cytoplasmic membranes. However, Staphylococcus cells treated with human beta-defensin 3 (hBD3) showed that inhibition of cell wall synthesis could be a significant part of the killing process.

Researchers also identified cell wall biosynthesis as the pathway selected by plectasin, but with an even higher affinity to Lipid II than hBD3. This mechanism is also found in bacterial lantibiotics and may be an important feature in the mode of action of different classes of AMPs, whose origin range from microorganisms to vertebrates.

Work carried out by the NAM project successfully showed that for natural antimicrobial substances of quite different origin all interfere with the same target, Lipid II, inhibiting the same cell wall biosynthesis pathway in the pathogen Staphylococcus aureus.

This knowledge will prove invaluable for the future development of novel antibiotics and in identifying new targets for them.