Multiple Drug Targets Identified for Gram-Negative Infections
Scientists have identified a set of genes that may represent new therapeutic targets for drug-resistant Acinetobacter baumannii infections, and potentially infections caused by other Gram-negative bacteria. The discovery, by researchers at the University at Buffalo, results from a set of studies designed to identify genes essential for the growth and survival of A. baumannii, a bacterium responsible for a growing number of potentially fatal hospital-acquired infections globally.
Compounding this A. baumannii infection problem is the fact that a number of strains are now resistant to all or nearly all antimicrobial drugs, but there are no new antimicrobial agents in development that are active against the bug, comments lead Buffalo researcher Thomas A. Russo, M.D. The team thus carried out a screen to identify genes that are essential for growth and survival of the bacterium and thus may represent new drug targets.
Genome-wide essentiality screens are usually performed on rich laboratory media, but the Buffalo researchers screen approach instead used human ascites to mimic conditions the bacterium is subjected to in vivo. “Laboratory conditions create a different type of environment from what happens in patients, where certain nutrients the bacteria need will be present in very low amounts and the where the bacteria encounter immune and inflammatory responses,” comments co-investigator Timothy C. Umland, Ph.D., professor of structural biology at the University at Buffalo School of Medicine and Biomedical Sciences. “We were purposely trying to test for genes that are important for growth in these more realistic conditions."
The screen identified 34 mutant A. baumannii strains with unique gene disruptions that demonstrated little or no growth on ascites. Subsequent evaluation of these strains in a rat subcutaneous abscess model found that 18 of the genes were in vivo essential. “The putative gene products all had annotated biological functions, represented unrecognized or underexploited antimicrobial targets, and could be grouped into five functional categories: metabolic, two-component signaling systems, DNA/RNA synthesis and regulation, protein transport, and structural,” the investigators report in their published paper in mBio.
Importantly, most of the 18 genes were missing from the current Database of Essential Genes (DEG), a catalogue of genes considered essential for bacterial growth, including those of Acinetobacter baylyi, which is closely related to A. baumannii. And none of the 18 genes, or their putative gene products, are the targets of either FDA-approved or developmental drugs. The team says the findings highlight the importance of screening for essential genes using clinically relevant media and in vivo validation. “This is a large set of genes that has been flying under the radar,” Dr. Russo states.
The newly identified genes may also be relevant as targets for other Gram-negative bacteria, professor Umland continues. “So far, our computational models show that these genes seem to be conserved across Gram-negative infections, meaning that they may lead to new drugs that would be effective for other drug-resistant infections as well.”
The researchers describe their results in a paper titled “In Vivo-Validated Essential Genes Identified in Acinetobacter baumannii by Using Human Ascites Overlap Poorly with Essential Genes Detected on Laboratory Media.”