In a recent study conducted by Mareike Saathoff and her team at Freie Universität Berlin, a fascinating discovery has been made regarding the antibiotic albicidin and its impact on infectious bacteria. This research, published in the open access journal PLOS Biology, sheds light on a significant increase in bacterial resistance to albicidin – up to an astonishing 1,000-fold – achieved through a novel gene amplification mechanism.
The escalating issue of bacterial resistance to antibiotics is responsible for millions of deaths globally each year. Gaining a deeper comprehension of how bacteria evolve to resist antibiotics is of paramount importance in the quest to develop more potent antibiotics and formulate effective usage strategies.
Albicidin has recently emerged as a promising antibiotic with the ability to target a wide array of bacterial species by disrupting their DNA replication process. Despite its potential, certain bacteria have demonstrated the ability to develop resistance against albicidin.
To delve further into the mechanisms behind albicidin resistance, Saathoff and her colleagues embarked on a series of experiments utilizing an extensive array of tools, including RNA sequencing, protein analysis, X-ray crystallography, and molecular modeling.
Their investigations unveiled that two prevalent bacteria implicated in human infections, namely Salmonella typhimurium and Escherichia coli, are able to acquire resistance to albicidin following exposure to escalating concentrations of the antibiotic. The root cause of this newfound resistance was traced back to an amplification in the number of copies of a specific gene, STM3175 (also known as YgiV), within the bacterial cells. This gene becomes increasingly amplified in each subsequent generation of cells as they multiply. STM3175 encodes a protein that interacts with albicidin, effectively shielding the bacteria from its deleterious effects.
Furthermore, additional experiments provided evidence that this resistance mechanism isn’t exclusive to the aforementioned bacteria. It is, in fact, widespread across various bacteria, both pathogenic and benign. Noteworthy examples include Vibrio vulnificus, which is capable of causing wound infections, and Pseudomonas aeruginosa, notorious for causing pneumonia and other infections. These findings carry substantial implications for the ongoing development of antibiotic strategies centered around albicidin.
In the authors’ own words, “Our study reveals a gene duplication and amplification-based mechanism of a transcriptional regulator in Gram-negative bacteria, that mediates resistance to the peptide antibiotic albicidin.”