China has a strong tradition as a supplier of raw materials used in many feed additives traded in the West. However, I have recently been involved with one of the few animal nutrition companies in China that works on creating its own technology, thanks to a team of scientists led by a researcher that was an Ph.D. student of Dr. Garry Allee, who in turn was an early student of the late Dr. D.H. Baker of University of Illinois, my own Ph.D. mentor.
Here, I want to present but a summary of how this Chinese company broke the mold and decided to approach the replacement of antimicrobial agents with a fresh look using their own technology and resources – something unusual based on my experiences.
Definition of AGPs and feed antibacterial agents
Most antibiotics for animals used as animal growth promoters (AGPs) were not absorbed well by the intestine, something beneficial as it ensured no residue in animal products and high concentrations in the hindgut. But the majority of those AGPs had a major drawback: They had limited antibacterial activity against gram-negative bacteria such as E. coli. And, for the feed and animal industry, it is actually this exact antibacterial activity against gram-negative bacteria that is most needed.
Based on research conducted for the better part of more than 10 years, a new concept has been created and, with permission, it is being shared here. The basic concept is rather simple: All feed additive compounds can have some antibacterial activity, but that may not be enough to replace antibacterial drugs. In other words, each antibacterial agent has a meaningful antibacterial effect at a different minimum inhibitory concentration (MIC). So, it is proposed that antibacterial property is a biochemical property of any compound (it may include even some nutrients) but it is the concentration that gives the desirable commercial antibacterial effect.
If an antimicrobial agent has a very unique structure, then its MIC can be very low, and its antimicrobial activity can be very strong. As an example, the MIC for benzoic acid is approximately 1,000 ppm. If it enters the hindgut of the animal at a concentration of at least 1,000 ppm, then will behave like a proper antimicrobial agent. If not, then it is not useful as an antimicrobial agent even though it possesses the basic antimicrobial property.
It can be said that the ban on AGPs is not a ban on the principle and mechanism of action of antibiotics, but rather a reactive mechanism to reduce cross-resistance as related to human antibiotics. So, it is still possible to follow the antibacterial principle of antibiotics to find suitable alternatives to AGPs. An understanding of the above requires an interdisciplinary perspective (nutrition, pharmacology, toxicology, microbiology, chemistry, etc.), which is often lacking in the industry and is one of the major causes of the confusion in the development of alternatives to AGPs.
How to replace antibiotics with feed antibacterial agents
The use of any feed antibacterial agent as an alternative to AGPs should follow a list of essential properties, such as strong and broad-spectrum antimicrobial properties, especially against gram-negative bacteria; no cross-resistance with antibiotics; no intestinal absorption leading to high hindgut concentration at relatively low dosage; generally recognized as safe (GRAS) as defined by the U.S. Food and Drug Administration (FDA); and application cost close to that of antibiotics. Ideally, successful products should satisfy all of the above simultaneously.
Based on proprietary research, it is proposed that there is a unique relationship between in-vitro MIC and the effective amount of each additive in the feed. In general, the effective amount of additive in the feed (ppm) is at least 3-5 times (it can be up to 10 times) the in-vitro MIC (ppm). This is a critical property which is rarely mentioned, but it is a key indicator for the development of efficient and economical alternatives to AGPs.
Systematic screening and comprehensive assessment methods for AGP alternatives
The screening process should start with the basic concept – the mechanism of action of each AGP. For example, compounds with similar antimicrobial efficacy compared with AGPs (targeting E. coli, Salmonella and Clostridium perfringens, etc.) are first tested and selected from a wide range of GRAS substances. Single-factor, high-dose challenge trials with AGPs (e.g. chlortetracycline) and alternatives to AGPs are then carried out in high-stress animal models, such as weaned piglets with diarrhea or broilers suffering from coccidiosis, to evaluate product efficacy. This is followed by screening in simple feed-and-weigh trials under practical commercial conditions. However, nutritionists should not base their decisions solely on a single trial, as is often the case. Instead, they should consider a group of trials where any compound is found to consistently provide a positive response.
Relying on simple feed-and-weigh trials alone to screen AGPs alternatives can be difficult, because of the long period required for repeating trials to verify results, and high demand for standardization and management of trial design and implementation, respectively. Therefore, challenge trials in high-stress animal models are the most direct way to verify the efficacy of alternatives to AGPs.
Examples of efficient alternatives developed with high-stress animal models
Based on the above, more than 3,000 compounds from various GRAS substances have been screened for antibacterial activity for more than 10 years. The antibacterial activity results were combined with metabolic processes and were extrapolated based on the original pharmacological properties. As an example, three examples are offered here for discussion.
1. Enteric-released myristic acid
Myristic acid has broad-spectrum antibacterial activity against major intestinal pathogens, including especially C. perfrigens and E. coli, which are main poultry pathogens. But, because myristic acid is a long-chain fatty acid, it is rapidly absorbed before reaching the hindgut. Enteric release delivers this acid at the point of the hindgut where it can exert its pharmacological property as an AGP.
2. Culture of Aspergillus niger
Secondary metabolites produced by Aspergillus niger (best if it is of food grade so as to be considered a GRAS-level product and their metabolites safe for use in animals) exhibit strong antimicrobial action. In our case, this has been shown to be the case under solid-state fermentation. The combination of the original fungus, its direct culture metabolites, and even in this case selected prebiotics to boost the performance of Aspergillus niger, provide another interesting proposal as a replacement to antibiotics, in which case we can refer to the phenomenon of synbiotics.
3. Enteric-released benzoic acid
Benzoic acid has the strongest antibacterial activity among similar organic acids. However, the bioavailability of benzoic acid in animals exceeds 80%, and only a very small part reaches the hindgut. Plus, straight benzoic acid has a very unpleasant smell. By using a specific enteric-release preparation process (not the coating products used for similar products), benzoic acid can be directly delivered in the hindgut to exert its antibacterial effect. In addition, it is possible for such a product to have anti-secretory effects that could ease diarrhea, a case considered separately from pathogenic diarrheas (for example, enterotoxins that cannot be addressed by conventional antibiotics).
Many may realize there is nothing unique in the generic names mentioned above. What is unique, in my own opinion, is a Chinese company undertaking the research and development steps to deliver a finished product instead of providing just the raw materials for others to do so. Whether their products work is up to the end user, as is always the case with any other product.