Bacterial hole-punch holds potential as novel antibiotic
New class of spiral polypeptide targets bacterial outer membrane
Antibiotic resistance is a growing problem globally, but a novel class of polypeptides developed at the University of Illinois (IL, USA) could offer a solution: targeting the outer membrane, a structure every bacterium needs to survive.
The short protein chain polypeptides act as hole-punchers perforating the bacterial membrane, causing the cell to fall apart. They are designed with a positively charged shell that lets them travel, unaffected by interactions with other proteins, through the body. The shell also attracts them to bacterial membranes.
Menghua Xiong, co-first author of the study, explained: “When you have an infection, it can be very difficult for a doctor to know which bacteria are infecting you. Many antimicrobial agents can only cure one class of bacteria. A doctor may try one class, and if that doesn’t work, try another class. We need more broad-spectrum antimicrobial agents.”
The novel antimicrobial polypeptides (AMPs) are designed to fold into a spiralling rod-like structure, which punches holes in the bacterial membrane. “We use a very set mechanism to puncture the bacterial membrane, so the polypeptides don’t really care whether the bacteria are gram positive or gram negative. They just kill the bacteria independent of their other surface properties,” described team leader Jianjun Cheng.
Polypeptides are hydrophobic, and do not travel well in bodily fluids. It was also challenging to find a way to prevent other molecules in the bacterium from interacting with, and disrupting, the polypeptide’s protein structure and rendering it ineffective. The research team addressed these barriers by attaching positively charged ions to the backbone of the protein, creating a protective shell to shield it from cross-reactions and to make it water-soluble. Once shielded, the molecule is protected from changes in temperature and pH, lending it stability and predictability. It is also has the advantage of targeting bacterial membranes, while the shell decreases interaction with human cells.
The AMPs developed have radial amphiphilicity and appear to offer several key advantages over conventional AMPs, for example stability against proteases and a simple design. The research team has demonstrated their high antibacterial activity against both gram negative and gram positive bacteria, and the polypeptides demonstrate low hemolytic activity, making them a potential general platform for developing future antimicrobial polypeptides to treat resistant bacterial infections.
The researchers plan to continue to improve the AMPs, working to make them precise in their targeting of pathogenic bacteria. Their pre-set design means that the team predicts that scaling up their production could be feasible.
Xiong, M., Lee, M. W., Mansbach, R. A., Song, Z., Bao, Y., Peek, R. M., … Cheng, J. (2015). Helical antimicrobial polypeptides with radial amphiphilicity. Proceedings of the National Academy of Sciences , 112 (43 ), 13155–13160. doi:10.1073/pnas.1507893112