Researchers from the University of Michigan Life Sciences Institute and School of Public Health have discovered a new class of chemical compounds that work to inhibit biofilm formation, thereby identifying a potential new therapeutic target for the treatment of infections caused by Acinetobacter baumannii
The team’s findings
, which were published in Nature Communications
, offer new promise in the ongoing battle against infections caused by antibiotic-resistant organisms. A. baumannii
is a multidrug-resistant bacteria associated with hospital-acquired infections, including ventilator-assisted pneumonia (VAP). A study published in 2009 linked the bacteria with nearly 20 percent of all VAP cases among patients admitted to intensive care units at European hospitals the previous year. The Centers for Disease Control and Prevention state
that, “A. baumannii
accounts for about 80% of reported infections.”
Earlier research has found that A. baumannii
grows on biofilms, a sheet-like structure that enables the bacteria to thrive and develop resistance to existing antimicrobial agents. The Michigan researchers, however, demonstrated that a chemical compound called cahuitamycins is capable of inhibiting biofilm formation. They were able to isolate the compound from the lab’s marine micro-organism-derived natural product extracts (NPEs) library using static- and flow-based high-throughput screening (HTS) assays. Their initial analysis yielded 31 active NPEs. After performing a second round of microbial biological activity analysis on the nine most potent extracts, the researchers identified Streptomyces gandocaensis
as being of particular interest “due to its ability to inhibit biofilm formation, but showing a limited effect on A. baumannii
The authors write that “regrowth of the wild-type S. gandocaensis
[in their lab] over several months showed complete loss of production of the active biofilm inhibitor molecules,” which led them to “pursue a ribosome engineering approach to restore and improve production of the active metabolites.” The approach yielded an “improved strain DHS287 of S. gandocaensis
… with restored stable production that generates several-fold increased quantities of active molecules compared with initial wild-type levels.” Subsequent genetic analysis revealed that this introduced a point mutation in the rpsL gene, which encodes the ribosomal protein S12, in the engineered strain.
The authors note that earlier studies have demonstrated that mutations in the S12 gene “render cells potentially more active for polypeptide synthesis under typical starvation conditions during the late growth phase.”
The team believe theirs is the first reported instance where complete loss of an active, but structurally uncharacterized NPE has been recovered using ribosome engineering. They write, “The application of the streptomycin resistance-mediated screening of the Streptomyces strain identified from HTS against A. baumannii
has yielded a novel structural class of biofilm inhibitors… Cahuitamycins A-E along with allied chemical entities with distinct biological activity provides a primary foundation for future medicinal chemistry and synthetic exploration towards the development of an efficacious drug to prevent or limit biofilm formation. These results establish a unique opportunity for developing and discovering new antibiotics from genetically engineered strains bearing inherent flexibility in pathway initiation processes. More importantly, given the simultaneous decline in antibiotic drug discovery and increased incidence of multidrug resistant bacteria, the cahuitamycins may represent a propitious starting point for discovery and development of new therapeutics against dangerous human pathogens involving biofilm formation.”
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.
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