Investigating Antimicrobial Alternatives for BRD

Background

Antibiotic resistance in livestock bacteria is constantly rising, but with no new antibiotic drugs coming to market, it will make treating diseases like BRD harder despite already costing producers time, money and production, not to mention being an animal welfare concern. An alternative solution to antibiotics to avoid making the issue of resistance worse could be antimicrobial peptides (AMPs). AMPs are naturally occurring proteins with antimicrobial activities. Both microbes and animals produce a variety of AMPs, and they can be “customized” to increase their activity for specific pathogens, including Mannheimia­ hemolytica a commonly occurring BRD-causing pathogen.  

Objectives

• To generate a novel Mannheimia-specific AMP

What they Did

This team discovered a broad set of microbial AMPs that can kill M. hemolytica and focused on modifying this AMP to make it more effective and selective against it in the lab. It was also important that they test whether these different versions of the AMP harm cattle cells. Following these examinations, the most promising versions were tested against a panel of drug resistant M. hemolytica obtained from feedlots.

What They Learned

By designing and testing a series of AMPs that were intended to target M. haemolytica and comparing them to other AMPs, the team yielded results that provided a series of lessons related to a family of AMPs known as the STIPs. A resounding lesson was that the intentional design strategy to specifically target M. haemolytica was not more effective than focusing on general AMP identity and activity. Nevertheless, what they learned will help to inform future development molecules to specifically target certain pathogens.

This team also learned that a specific end of the STIPs, the beginning of the peptide known as the N-terminus, was important for activity against M. haemolytica. In fact, the introduction of additional positive charge at this end improved specificity for the BRD pathogen – meaning it was much better at targeting M. haemolytica without impacting other cells or bacteria. The significance of this area of the peptide was also shown when adding fat-loving molecules , which resulted in lower specificity for M. haemolytica and increased the toxicity to cattle cells. This means great care needs to be taken when developing AMPs as toxicity and specificity appear to be closely linked.

What It Means

Rational design of AMPs is a challenging task. A collection of AMPs modified to specifically target M. haemolytica did not yield better AMPs than the test designed to simply understand the structure and function of the molecules themselves. Regardless, there were certain modifications done that did make AMPs more selective for M. haemolytica over other important BRD pathogens like S. aureus, and others that influenced toxicity, though they are closely linked. In order to get AMPs effective enough to be used commercially, science needs to better understand the basics of their structure and how they function in cattle and how that compares to conventional antibiotics. Also, gaining insight on  how AMPs work to actually inhibit M. haemolytica will mean more impactful modifications and, ultimately, more effective and selective antimicrobials.