Researchers at the Rockefeller University and a pharmaceutical company have developed a new antibiotic that kills a wide range of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus anthracis, the bacteria that causes anthrax.
According to their paper published in the journal PLoS ONE, the antibiotic called Epimerox targets weaknesses in bacteria that have long been exploited by viruses that attack them, known as phage.
Target selection is critical for the development of new antimicrobial agents. To date, most approaches for target selection have focused on the importance of bacterial survival. However, in addition to survival, scientists believe that molecular targets should be identified by determining which cellular pathways have a low probability for developing resistance.
“For a billion years, phages repeatedly have infected populations of bacteria, and during this period of time they have identified weaknesses in the bacterial armor,” said senior author Prof Vincent Fischetti from the Rockefeller University’s Laboratory of Bacterial Pathogenesis and Immunology. “We’re taking advantage of what phage have ‘learned’ during this period for us to identify new antibiotic targets that we believe will escape the problem of resistance found for other antibiotics.”
The path to identification of this new target spanned more than seven years of effort. The team used a phage-encoded molecule to identify a bacterial target enzyme called 2-epimerase, which is used by Bacillus anthracis to synthesize an essential cell wall structure.
Based on a 2008 study, the team identified a previously unknown regulatory mechanism in 2-epimerase that involves direct interaction between one substrate molecule in the enzyme’s active site and another in the enzyme’s allosteric site. They chose to target the allosteric site of 2-epimerase to develop inhibitory compounds, because it is found in other bacterial 2-epimerases but not in the human equivalent of the enzyme. Through the collaboration with a pharmaceutical company, an inhibitor of 2-epimerase named Epimerox was developed.
First study author Dr Raymond Schuch tested the inhibitor in mice infected with Bacillus anthracis. He found that not only did Epimerox protect the animals from anthrax, but the bacteria did not develop resistance to the inhibitor.
The team also found that Epimerox was able to kill drug-resistant Staphylococcus aureus with no evidence of resistance even after extensive testing.
“Since nearly all Gram-positive bacteria contain 2-epimerase, we believe that Epimerox should be an effective broad-range antibiotic agent,” Prof Fischetti said.
“The long-term evolutionary interaction between phage and bacteria has allowed us to identify targets that bacteria cannot easily change or circumvent. That finding gives us confidence that the probability for developing resistance to Epimerox is rather low, thereby enabling treatment of infections caused by multi-drug-resistant bacteria such as MRSA. It is a very encouraging result at a time when antibiotic resistance is a major health concern.”
Bibliographic information: Schuch R et al. 2013. Use of a Bacteriophage Lysin to Identify a Novel Target for Antimicrobial Development. PLoS ONE 8(4): e60754; doi: 10.1371/journal.pone.0060754