The continuous rise of multidrug-resistant (MDR) bacterial strains has precipitated a global antibiotics crisis. Bacterial infections that were once routinely remediable have now become untreatable, resulting in elevated mortality and morbidity rates. Recognizing the severity of the global MDR challenge, the World Health Organization (WHO) and the Centers for Disease Control (CDC) have identified it as a top-priority healthcare concern.
A primary driver of bacterial multidrug resistance is the Multiple Antibiotic Resistance (MAR) pathway, governed by the MAR operon. Widespread in many bacterial species, this genetic circuit orchestrates the expression of numerous genes that diminish antibiotic efficacy through various mechanisms. Deciphering the mechanisms that regulate the MAR pathway is of paramount clinical relevance and importance.
In preliminary research, we discovered a novel mechanism for MAR pathway activation and subsequent multidrug resistance. This mechanism hinges on a three-gene cluster encoding the AZY proteins, specializing in copper handling and delivery. Our goal is to understand how the AZY proteins regulate the MAR pathway and contribute to bacterial multidrug resistance. Our preliminary findings underscore the potential impact of this research, revealing for the first time that copper delivery by the AZY proteins is essential for the activation of the MAR system and subsequent resistance to multiple antibiotics.