Publish date: 22.05.2017
The search for new antibiotics capable of fighting drug resistant bacteria is a major challenge for drug discovery scientists in academia and industry.
Gram-negative bacteria, unlike Gram-positive bacteria, in addition to having a cell wall and inner membrane, has an outer membrane, which makes it much more difficult for a drug to get inside the bacterial cell. That is why, in spite of intensive search for new chemical entities, no new classes of antibiotics were introduced against the Gram-negative bacteria since 1968. On the other hand, there are a number of antibiotics active only against Gram-positive bacteria.
Attempts to modify these compounds in order to gain activity against the Gram-negative bacteria were mostly unsuccessful due to lack of proper understanding of what physical chemical properties the drug should possess in order to be active against the Gram-negative bacteria.
In the recent paper, "Predictive compound accumulation rules yield a broad-spectrum antibiotic", published in Nature by Michelle F. Richter et al. (Nature, London, UK, 2017, doi: 10.1038/nature22308) the group of chemists from the University of Illinois (USA) reported results of their study on accumulation of more than 150 diverse chemical compounds in E. coli.
Analysis of these data shows that several factors affect the efficiency of the accumulation of chemical compounds in bacterial cell. Аmphiphilic molecules with primary amino groups, rigid molecular structure and high globularity showed the highest efficiency accumulation.
Based on conclusions they made, the authors of this publication experimentally proved that after the corresponding modification, the antibiotic that is active only against Gram-positive bacteria can gain activity against Gram-negative bacteria and thus become a broad-spectrum antibiotic. By introducing a primary amino group in compound (I) they synthesized the new compound (II).
While compound (I) was active only against the Gram-positive bacteria, the new compound (II) showed a broad-spectrum activity against both Gram-positive and Gram-negative bacteria.
This approach can lead to fast discovery of a number of new antibiotics active against Gram-negative bacteria.
Alexander Zhivich, Ph. D.
Framingham State University, Framingham, MA, USA