The hunt for new antibiotics and antimicrobial alternatives

The search for new antibiotics is a matter of global importance. The world is facing a shortfall in antibiotics. This is due to the accelerating rate of antibiotic resistance among certain pathogenic bacteria. Many of these pathogens pose a particular risk to people who have undergone surgery and to those who have a weak or suppressed immune system ('immunocompromised.') Many infections from antibiotic resistant bacteria can emerge in hospital (hence the term 'hospital acquired infection'; although there are also other community-based concerns.)

In this post, I'm taking an overview of some of the recent initiatives in the hunt for new antibiotics and antibiotics alternatives.

There are three areas that I'm focusing on:

• The use of robots to screen potential antibiotic alternatives;

• The use of mathematical algorithms to work out which new compounds might make the best drug candidates;

• The development of so-termed 'resistance breakers' - compounds designed to help existing antibiotics to work better.

Robotics

To help with the research for new compounds, scientists have created two robotic chemical-synthesizing machines.

The new devices have been named Symphony X and Overture. The main task of the machines is to create nanoscale biological structures that mimic the way that natural antibiotics work. With this the machines are creating peptoids, which are synthetic peptides. Recently peptoids have been developed as potential drugs for a range of different biomedical applications; this includes anti-microbial agents of the type that could be used as antibiotics. In the human body, the body manufacturers peptides to help with infections. These are not always effective and to fight certain pathogens antibiotics are administered.

The hunt for new antibiotics is an issue of global importance. The number of available compounds has not grown significantly for several decades and many bacterial pathogens are becoming resistant to those compounds that are available. This presents a risk to people with exposed wounds.

The research into peptoids is designed to complement the hunt for new antibiotics and it is for this reason that research has gone into robotics. Given the thousands of different chemical combinations, the use of robots helps scientists to screen various possible substances. As a sign of success, researchers at Roskilde University (Denmark) have used Symphony X and Overture to make various peptoids designed to target specific bacteria. The main mechanism is to target the bacterial cell wall and puncture it, allowing the contents to spill out and there by killing the bacterium.

This research has been published in the journal Antimicrobial Agents Chemotherapy, in a paper called “Structure-activity relationship study of novel peptoids that mimic the structure of antimicrobial peptides.”

The new robots are currently located at the Science User Facility at Berkeley Laboratory; here various streams of research are on-going.

The art of mathematics

The proposal to use math to help find the answer to new antibiotics has been put forwards by Miriam Barlow and colleagues, from University of California. Essentially the new work involves the use of a special algorithm to decoded how bacterial genes create resistance. By deploying a 'Correlated Probability Model', researchers have focused on 15 β-lactam antibiotics.

The idea is to find ways to roll-time back, in a sense, and to find ways to make bacteria no longer resistant to antibiotics. This centers on findings ways to undo the mutations that have caused the resistance in the first place.

Talking with Scientific American, Barlow explains "We were pushing evolution forward, trying to predict how antibiotic resistance would evolve, and we saw a lot of trade-offs."

The new research has been reported to the journal PLOS One, in a paper titled "Rational Design of Antibiotic Treatment Plans: A Treatment Strategy for Managing Evolution and Reversing Resistance."

Resistance breakers

One interesting area of research to assist with the battle against antibiotic resistant bacteria is with "resistance breakers." This is a term for compounds that function to boost the effectiveness of existing antibiotics.

In a new development, the company Helperby Therapeutics, a spin-out company founded by Professor Anthony Coates, St George's, University of London (U.K.), has created a resistance breaker that acts against the superbug MRSA (meticillin-resistant Staphylococcus aureus.)

The compound is called HT61. HT61 is a small quinolone-derived compound. It is is active against non-multiplying bacteria. The mechanism of action of the drug is to disrupt the bacterial cell membrane and destruction of the cell wall: essentially punching holes in the membranes of bacterial cells.

The chemical will soon go into clinical trials in India. Here tests are being developed, the BBC reports, under special licence by Cadila Pharmaceuticals, an Indian biotech company. The development is as a topical agent (to be used on the surface of the skin.)

The reason that there is medical interest in resistance blockers is because developing these chemicals is far less costly than seeking to discover entirely new antibiotics. Finding new antibiotics is slow and expensive. In some positive news on this front, a research group from Northeastern University in Boston, Massachusetts, have discovered 25 potential new antibiotics from soil samples. One of the compounds, called teixobactin, has been shown to be effective against tuberculosis and MRSA.

Finally, in some related news, an economist has called upon on the world's leading pharmaceutical companies to set up a $2 billion slush-fund to provide resources to universities so that microbiology departments can undertake research into new antibiotics.

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