decades to enhance the antibiotic’s potency, without much success.
Romesberg’s team showed that the pathogens that are resistant to arylomycin shared a key feature—a mutation in the binding site of an essential enzyme (Signal Peptidase) that sits on the surface (or just within it) of both Gram-positive and Gram-negative bacteria. Romesberg has suggested that the mutation, which added a floppy proline amino acid in the pocket of the binding site, was an adaptation that bacteria evolved millions of years ago as a defense against arylomycin.
Arylomycin binds to the enzyme and blocks its enzymatic activity, which is crucial for the microbes to survive. Romesberg’s team found that bacteria without the mutation are potently killed by arylomycin. More importantly, though, Romesberg said their research showed that arylomycin could be “optimized” to overcome and kill bacteria carrying the mutation that usually protects against arylomycin.
In other words, with a few tweaks to improve the molecule’s affinity for binding with a particular enzyme, arylomycin could represents a new class of broad-spectrum antibiotics that would be effective against a variety of infections, including those caused by MRSA and other drug-resistant pathogens.
Turner says the significance of Romesberg’s breakthrough was obvious. No fundamentally new class of broad-spectrum antibiotics has been developed since the quinolones were introduced to the clinic in 1962. And drug-resistant bacteria have never seen an antibiotic like this, he says.
Turner describes Romesberg’s discovery as exactly the sort of fundamental breakthrough that Avalon founder Kevin Kinsella seeks to invest in. Another key factor in deciding to start RQx, he says, was that Romesberg had done it before. He was a founder in Achaogen, an eight-year-old biopharmaceutical in South San Francisco focused on