Search for new antibiotics intensifies

Bacteria and enzymes are key contenders in battle against superbugs.

As hospitals struggle to deal with superbugs and antibiotic resistance, the search for new antibiotics has a huge sense of urgency. Now two independent teams of researchers have discovered possible new antibiotics. The first suggests using the predatory bacterium Bdellovibrio as a ’living antibiotic’. The second has characterised an enzyme which can turn a small peptide into a potent lanthionine-containing antibiotic or lantibiotic; such compounds are used as natural preservatives in a variety of foods, including milk, cheese, meat, and canned vegetables, and do not seem to induce bacterial resistance.

A team at the Max-Planck-Institute for Developmental Biology in Germany, together with colleagues from the universities of Nottingham, UK, and Bielefeld, Germany, has unravelled the complete gene sequence of the predatory bacterium, Bdellovibriobacteriovorus, and used the knowledge to study the life cycle of this unique bacterium.

Bdelliovibrio initially locates its prey using its chemosensory system and attaches itself reversibly while verifying its suitability for invasion. By using a lytic cocktail capable of degrading lipids, proteins and carbohydrates, Bdellovibrio generates an opening in the cell wall of its prey. The bacterium can remain encysted in the periplasmic space between the outer and inner membranes of the prey cell, but generally enters its growth phase immediately, using nutrients in the prey cell to elongate itself and consume the prey’s cytoplasm. During the life cycle of the Bdellovibrio, the bacteria differentiate into as many as 15 motile cells, which seek out and attack new prey.

The researchers are now attempting to identify the targets in the prey cell; the lytic enzymes acting on cellular systems that are not targeted by conventional antibiotics would be especially interesting because they could lead to the use of Bdellovibrio as a ’living antibiotic’.

Meanwhile, chemists from the University of Illinois at Urbana-Champaign, US, have explored another avenue in the search for new antibiotics. Wilfred van der Donk and his colleagues have characterised the in vitro activity of an enzyme, LctM, responsible for turning a small protein precursor into the potent lantibiotic lacticin 481. LctM performs a series of dehydrations and cyclisations on the peptide precursor to produce mature, active lacticin 481. LctM can act on versions of lacticin 481 precursor peptides that are truncated or that contain different peptide subunits, suggesting that it could be used with semi-synthetic substrate peptides to create new lacticin analogs. Lantibiotics such as nisin are effective and elude resistance because they work like a two-edged sword. They form holes in the cell membrane and at the same time bind to intermediate targets of a disease-causing bacterium. ’Hitting two targets simultaneously reduces the risk of resistance occurring,’ says van der Donk.

Hamish Kidd