The race for new antibiotics

Researchers and doctors from the immigrant communities are engaged in attempts to develop drugs that will act on particularly violent "super bacteria" that have developed resistance to the antibiotics available today

By: Dr. Dina Zafariri, Galileo

In the race between the drug developers and the bacteria that develop resistance against them, an achievement was recorded for man, with the discovery of a new antibiotic: the Nature newspaper published an article by Jun Wang and his colleagues from the research laboratories of the Merck company in New Jersey. The article deals with their new discovery, which provides an answer to the new strain of Staphylococcus aureus. This "superbug", which appeared in 1996, is resistant to all known types of antibiotics, and poses a serious threat to those hospitalized.

In the United States, it is reported that 90 hospitalized patients contract infections in hospitals each year; Drug-resistant bacteria are responsible for 75% of the deaths of these patients. The ever-increasing threat of infections originating from antibiotic-resistant bacteria, due to their widespread use in hospitals, necessitates a race to find new types of antibiotics that work by mechanisms different from the known ones. In the hospitals, resistant strains of staphylococcus were created, called MRSA - methicillin-resistant S. aureus and MDR - drug-resistant-multiple, meaning, respectively, Staphylococcus aureus is resistant to the antibiotic methicillin, or has resistance to many types of antibiotics. Resistant strains of enterococci have also appeared. Staphylococcus and enterococcus are types of bacteria from the gram-positive group (see box), which cause pneumonia and other fatal diseases. Most of the time, Staphylococcus aureus is a harmless bacterium, found on the skin of healthy people. Only when it penetrates a wound in the body or the respiratory system, it causes a serious risk and may even lead to death.

A war on several fronts

The first front on which the war against bacteria was focused was the wall unique only to bacteria, which allowed a unique damage to the bacteria, without causing direct damage to the body of the host. The "weapons" at the front were the penicillins, which were aimed mainly against the gram-positive, thick-walled bacteria; First produced in 1941.

The structure of penicillin compounds, including methicillin, includes a beta-lactam ring (-Lactam b). This ring has a structure similar to the structure found at the end of the pentapeptide in the newly synthesized wall layer. The enzyme transpeptidase, which binds, during normal wall formation, to this structure, instead binds to the beta-lactam ring of penicillin; The new layer in the wall is not connected to the previous ones, and the creation of the wall is damaged.

Over time, the bacteria developed systems that made them resistant to methicillin and other semi-synthetic penicillin derivatives. Some of these systems include an enzyme that breaks down the beta-lactam ring of the antibiotic; Others include a transpeptidase whose binding efficiency to the beta-lactam ring is much lower than that of the original enzyme.

With the discovery of the MRSA strain, the antibiotic Vancomycin was developed, which although works at the same junction of creating the bridges in the wall, but instead of binding to the enzyme, it binds to the substrate, i.e. - to the wall itself. The doctors and researchers were not surprised to discover that following the transition to widespread use of vancomycin, strains of MRSA resistant to vancomycin - VRSA - appeared and were isolated. The main factor that gave these strains their resistance is a thicker wall than the cell wall of the wild strain.

A bacterium endowed with the ability to produce certain enzymes, which give it resistance to drugs, does not only pass it on to its offspring; He may also transfer this ability to other bacteria. This transition is done using plasmids (small circular DNA segments, which are in the bacterial cell separately from the chromosome) or transposons - "jumping genes".

The "super bacteria" has developed resistance

Despite the urgent need for new types of antibiotics, with different mechanisms of action, only two new families of antibiotics have been developed over the past 40 years. Unfortunately, the "superbug" has developed resistance against them as well.

One family of new antibiotic drugs, the oxazolidinone family, to which the antibiotic linezolid belongs, is the only group of antibiotics that is not of natural origin. The compound was designed to interfere with the initial step of protein synthesis. The compound was synthesized for the first time, to the researchers' delight, in 1996, at the same time as the discovery of the resistance acquired by the staphylococcus bacterium against all penicillin derivatives, and was approved and entered into wide use in 2000.

Antibiotic drugs from this family are designed to bind to one of the subunits that make up the bacterium's ribosome, aka the structure responsible for synthesizing proteins from amino acids, to damage its function and in this way damage the essential process of protein synthesis.

The drugs from the oxazolidinone family did also kill the staphylococcus bacteria from the MRSA strain, but as early as 2001 strains of MRSA appeared that were also resistant to the oxazolidinone family, and in their wake more resistant bacteria appeared. The second family of new antibiotic drugs developed is a group of natural lipopeptides secreted by the bacterium Streptomyces roseosporus. A lipopeptide is a compound consisting of a chain of amino acids to which a lipid tail is attached. To this group belongs the compound daptomycin, a circular lipopeptide (like the other lipopeptides produced by this bacterium).

When the lipopeptide daptomycin enters the bacterial wall, the lipid tail penetrates the bacterial membrane and causes rapid electrical depolarization of the membrane and the release of potassium ions. As a result, the synthesis of DNA, RNA and proteins in the cell stops, and the bacterium dies. Until the time of writing the news, no bacteria resistant to this antibiotic have been found. The drug works against aerobic and non-aerobic gram-positive bacteria. However, due to the fatty structure of the molecule, this medicine can only be used for the treatment of external wounds and ulcers, and not for internal treatment, when taken orally.

And here, a new hope was born. Jun Weng's publication on behalf of the Merck company reports on a new family of antibiotic drugs that work effectively against MDR strains of enterococci and staphylococci.

The researchers at the company scanned 250,000 extracts from microorganisms that secrete antibacterial substances. A series of comprehensive studies, which included bacterial genetics, biochemistry, drug research and structural biology, led to the discovery of a new small compound, known as Platensimycin and derived from the bacterium Streptomyces platensis. This bacterium was isolated from the soil in South Africa.

The compound platansamycin attacks the key enzyme in the synthesis pathway of the long fatty acids in bacteria, which are the building blocks of the membranes in the bacteria, and especially in the outer membrane, outside the wall, which strengthens the wall. The enzyme in bacteria is not similar to that in mammals, and therefore the antibiotic attack is unique to the bacterial pathway.

The effectiveness of the new antibiotics has so far only been proven in mice infections, and there is still a long way to go until they pass the stages of preclinical and clinical trials in humans. Nevertheless, platansamycin - which is derived from a bacterium - is currently considered the most effective antibiotic and an encouraging discovery in the exhausting and ceaseless race between us and the bacteria.

According to Eric Brown, a microbiologist at McMaster University in Hamilton, Canada, this is great promise in a field that has been disappointing and unpromising. According to Brown, the discovery shows how much wisdom nature invests in the search for enzyme activity inhibitors.

Gram-positive bacteria

Gram staining is a staining developed in 1884 by the Danish doctor Hans Christian Gram (Gram). This staining distinguishes between two main groups of bacteria, which are therefore called "gram-positive" and "gram-negative". The staining is based on the differences in the wall thickness of the bacteria. A main component of the wall is peptidoglycan, which is built from repeating units of two sugars: N-acetyl glucose-amine and N-acetyl muramic acid. A pentapeptide consisting of five amino acids is attached to the mormic acid.

The main difference between gram-positive and gram-negative bacteria is the wall thickness. In gram-positive bacteria, the wall constitutes 90% of the dry weight of the envelope surrounding the bacterium, while in gram-negative bacteria - about 10-5% of the weight. The thickness of the wall and its stability in Gram-positive bacteria are responsible for bridges consisting of five units of the amino acid glycine, which connect the amino acid chains.