"HUMANISTIKA" JOURNAL
An Interview with Dr. Manuel Varela: Antimicrobials and their Impact
Michael F. Shaughnessy
Manuel Varela is a native New Mexican, born and raised in Santa Fe. As a Ph.D. student at UNM, Varela studied antibiotic resistance and found evidence for the functional role of an amino acid sequence motif that’s highly conserved in antibiotic efflux pumps.
After graduation, Varela went to Harvard as a postdoctoral fellow and studied the lactose permease from Escherichia coli in the laboratory of Prof. Thomas Wilson. Varela returned to New Mexico as a faculty at ENMU to teach microbiology and conduct research on bacterial transporters and antibiotic resistance.
Since promotion to professor in 2008, Dr. Varela has published numerous primary papers in peer-refereed journals, plus review articles and book chapters.
The Varela research laboratory is interested in molecular microbial physiology of bacterial resistance to antimicrobial agents. They study bacterial multidrug efflux pumps from the major facilitator superfamily of solute transporters. His laboratory discovered the multidrug efflux pumps LmrS from Staphylococcus aureus and EmrD-3 from Vibrio cholerae.
1) Dr. Varela, recently you published an article indicating some concern about the food production environment in the U.S. and around the world. What are your main concerns?
In general, food is quite safe, especially in areas where the quality of life is good. There are, however, relatively fewer instances when food becomes a vehicle for infectious disease causation and transmission to other individuals. In these instances, food may be inadequately prepared or contaminated with bacterial pathogens. It is estimated that over 30 million food-associated illness occur annually in the U.S., with about 3.6 million of these being due to bacterial food-borne pathogens. On a worldwide scale, these numbers are obviously higher.
My main concerns lie with the use of antimicrobial agents for purposes other than infectious disease treatment. Microbes in nature exist in populations of variants, each individual microbe of which may be susceptible to antimicrobial agents to widely varying degrees. When antimicrobial agents are applied to these microbial populations of bacteria, the antimicrobials will inhibit the growth or kill the susceptible bacterial microbes, leaving behind the bacterial variants which are less susceptible, or even resistant, to the antimicrobial agent used.
These antimicrobial resistant bacteria may then predominate in their local environments, as their less susceptible bacterial colleagues aren’t around to compete for resources. Interestingly, it is frequently observed that bacterial variants that are selected for antimicrobial resistance in this way are actually resistant to multiple antimicrobial agents to which the bacteria had not been previously exposed. If such multi-antimicrobial resistant bacteria are agents of food-borne illness in patients, they may be more difficult to treat effectively.
Antimicrobial agents are used in food production environments for treatment of infectious disease in food animals, for prevention of infectious disease (called prophylaxis) in food animals, and for the promotion of growth in food animals. Selection of bacterial variants which are resistant to one or more antimicrobial agents may be transmitted to other individuals.
Furthermore, bacteria have developed means to transfer their genes encoding antimicrobial resistance mechanisms to other bacteria. These DNA transfers between unrelated bacterial species may readily occur in the animal gut, where thousands, if not millions, of bacterial species are thought to reside.
2) Now, what exactly are food-borne pathogens?
Food-borne pathogens are microbes that are agents of infectious disease and intoxication (i.e., food-poisoning) and which are passed onto humans by contaminated foods or foods that are poorly cooked or improperly prepared. Such illnesses due to food-borne pathogens range from mild to relatively serious, depending on the nature of the microbe and the susceptibility of the human host. Food-borne pathogens may be serious concerns worldwide, especially in areas where living conditions or sanitation are chronically poor.
3) I think that we all know that overuse of antibiotics has resulted in some serious consequences. What are some of these consequences?
Examples of overuse and misuse of antibiotics include 1) not fully completing the course of treatment for bacterial infectious disease as prescribed by the physician and 2) using antibiotics for infections caused by viruses, as antibiotics are not effective against viruses. In both human clinical and agricultural settings, use of antimicrobial agents, such as antibiotics, has led to the selection of bacterial variants which are resistant to the antibiotics used. One consequence is that the selected bacterial variants are frequently also resistant to multiple antibiotics.
Another consequence is that the resistant and multiple-antibiotic resistant bacteria transfer their DNA harboring resistance genes to different species of bacteria. These resistant bacteria may transfer to others by person-to-person transmission and by food-borne modes of transmission. These multi-antibiotic resistant bacteria are becoming increasingly difficult to treat when they are causative agents of infectious disease in humans, especially in patients who are young, elderly or immune-compromised.
4) It was a while ago, but I recall studying Salmonella, Campylobacter, and Staphylococcus aureus, and Escherichia in some undergraduate science classes. But for our readership, can you describe each of these and why they are important?
Each of these bacteria may cause infectious disease, depending on the nature of the microbe and the circumstances of their interactions with humans. The bacterium, Salmonella enterica, is the causative agent of salmonellosis, such as typhoid fever, gastroenteritis and septicemia. This bacterium has been historically notorious, as typhoid fever has been included in the classic literature, like Great Expectations, by Charles Dickens. Additionally, S. enterica was responsible for the death of Louis Pasteur’s daughter, Cecile, in 1866 at the age of 12 years, from the typhoid fever.
The bacterium Campylobacter jejuni is a serious causative agent of acute gastroenteritis, especially where sewage contamination occurs, like that seen in floods. The Staphylococcus aureus bacterium has several variants which are methicillin-resistant (MRSA) and vancomycin-resistant (VRSA). These bacteria have been serious causes of healthcare facility- (HASA) and community-acquired (CASA) S. aureus infectious disease, because of their multidrug resistant natures.
The well-known and intensely studied Escherichia coli, on the other hand, is actually harmless as it resides in the gut of all animals, including all humans; these E. coli are used for basic research, like gene-cloning, for genomics, physiology, and biochemistry, for instance. The presence of E. coli anywhere outside of the laboratory, however, is an indicator of fecal contamination. There are, however, a handful of E. coli variants that are quite serious in their pathogenesis. These E. coli variants have wreaked havoc in human populations for many decades. One infamous E. coli pathogen, called strain O157:H7, was responsible for the so-called “Jack in the Box” outbreak involving contaminated beef and hundreds of deaths.
5) Some countries have banned the use of antibiotic growth promoters. Why is this important?
Due to the accumulated wealth of published data in peer-reviewed journals definitively documenting the association between the use of antimicrobial agents in agriculture and the development of transferable multidrug resistance genetic elements in bacteria, several antimicrobial agents have been banned in agriculture, especially in Europe, but also to a lesser extent in the U.S. The bans have resulted in no serious consequence to food production efficiency and to decreases in the incidence of certain resistant bacterial pathogens. The issue remains controversial, however, as consultants and officials from pharmaceutical companies are concerned about revenue and antimicrobial agent sales to the agriculture industry.
6) Now what exactly is an antimicrobial? And why are they important?
Antimicrobials are agents that kill and inhibit the growth of microbes. They are important for controlling microbes so that they do not result in contamination or incur infectious disease.
There are two general types of antimicrobials. The first type is physical in nature and includes agents such as heat and radiation, like X-rays or gamma radiation. The second type is chemical in nature, and includes agents which may be used for disinfection of inanimate surfaces, antisepsis of living tissue, or chemotherapeutically, such as with an antibiotic prescription for the treatment of a bacterial infection.
7) Now, what exactly do you mean by "human pathogens" or animal origin? And are there specific animals of concern?
By “human pathogen” we mean microbes that cause morbidity (disease) and mortality (death) in humans. Such microbes are pathogenic to humans. The term pathogenesis refers to the generation of disease. With respect to animals, there is concern that they (animals) may transmit microbial infections to humans.
Such microbial infections that are transmitted from animals to humans are referred to as zoonoses. Probably the animals of most concern involve those who have the most contact with humans. Interestingly, animals with little or no contact with humans obviously do not constitute a danger of infectious disease transmission. In cases of environmental encroachment and disruption by humans or by climate change, however, the chances of encountering these remote animals may be enhanced. The consequences of these interactions remain to be seen.
8) Why do we need a concerted global effort to minimize the use of antimicrobials?
It is widely believed by expert investigators in the field that minimization of antimicrobial use will foster conditions that thwart or circumvent the emergence of drug- and multidrug-resistant bacteria. If such were to be the case, then it is thought that clinically relevant antimicrobial agents that have been compromised by drug- and multi-drug resistant bacterial pathogens may once again be effective for treatment.
Such antimicrobial minimization might include using antibiotics only for clinical bacterial disease and finishing the entire course of antibiotic treatment for bacterial infections. Such programs of antimicrobial stewardship and prudent use of antimicrobials are ongoing and gaining a foothold, especially in clinical settings.
9) Where was your article published, and what have I neglected to ask?
Our peer-reviewed review article was accepted for publication in the scientific journal called Microorganisms and published March 14, 2017. The review briefly summarizes the history of antimicrobials, the various mechanisms of bacterial resistance to antimicrobials, the uses of antimicrobials in agriculture, the emergences and development of bacterial resistance in food production environments, and the efforts being performed in order to reduce conditions that foster emergence and spread of antimicrobial resistance. The review article is available online:
Abstract: http://www.mdpi.com/2076-2607/5/1/11/
PDF Version: http://www.mdpi.com/2076-2607/5/1/11/pdf
Title: The Food Production Environment and the Development of Antimicrobial Resistance in Human Pathogens of Animal Origin
Abstract: Food-borne pathogens are a serious human health concern worldwide, and the emergence of antibiotic resistant food pathogens has further confounded this problem. Once highly efficacious antibiotics are gradually becoming ineffective against many important pathogens resulting in severe treatment crises. Among several reasons for the development and spread of antimicrobial resistance, their overuse in animal food production systems for purposes other than treatment of infections is prominent. Many pathogens of animals are zoonotic, and therefore any development of resistance in pathogens associated with food animals can spread to humans through the food chain. Human infections by antibiotic resistant pathogens such as Campylobacter spp., Salmonella spp., Escherichia coli and Staphylococcus aureus are increasing. Considering the human health risk due to emerging antibiotic resistance in food animal-associated bacteria, many countries have banned the use of antibiotic growth promoters and the application in animals of antibiotics critically important in human medicine. Concerted global efforts are necessary to minimize the use of antimicrobials in food animals in order to control the development of antibiotic resistance in these systems and their spread to humans via food and water.
Michael F. Shaughnessy
Manuel Varela is a native New Mexican, born and raised in Santa Fe. As a Ph.D. student at UNM, Varela studied antibiotic resistance and found evidence for the functional role of an amino acid sequence motif that’s highly conserved in antibiotic efflux pumps.
After graduation, Varela went to Harvard as a postdoctoral fellow and studied the lactose permease from Escherichia coli in the laboratory of Prof. Thomas Wilson. Varela returned to New Mexico as a faculty at ENMU to teach microbiology and conduct research on bacterial transporters and antibiotic resistance.
Since promotion to professor in 2008, Dr. Varela has published numerous primary papers in peer-refereed journals, plus review articles and book chapters.
The Varela research laboratory is interested in molecular microbial physiology of bacterial resistance to antimicrobial agents. They study bacterial multidrug efflux pumps from the major facilitator superfamily of solute transporters. His laboratory discovered the multidrug efflux pumps LmrS from Staphylococcus aureus and EmrD-3 from Vibrio cholerae.
1) Dr. Varela, recently you published an article indicating some concern about the food production environment in the U.S. and around the world. What are your main concerns?
In general, food is quite safe, especially in areas where the quality of life is good. There are, however, relatively fewer instances when food becomes a vehicle for infectious disease causation and transmission to other individuals. In these instances, food may be inadequately prepared or contaminated with bacterial pathogens. It is estimated that over 30 million food-associated illness occur annually in the U.S., with about 3.6 million of these being due to bacterial food-borne pathogens. On a worldwide scale, these numbers are obviously higher.
My main concerns lie with the use of antimicrobial agents for purposes other than infectious disease treatment. Microbes in nature exist in populations of variants, each individual microbe of which may be susceptible to antimicrobial agents to widely varying degrees. When antimicrobial agents are applied to these microbial populations of bacteria, the antimicrobials will inhibit the growth or kill the susceptible bacterial microbes, leaving behind the bacterial variants which are less susceptible, or even resistant, to the antimicrobial agent used.
These antimicrobial resistant bacteria may then predominate in their local environments, as their less susceptible bacterial colleagues aren’t around to compete for resources. Interestingly, it is frequently observed that bacterial variants that are selected for antimicrobial resistance in this way are actually resistant to multiple antimicrobial agents to which the bacteria had not been previously exposed. If such multi-antimicrobial resistant bacteria are agents of food-borne illness in patients, they may be more difficult to treat effectively.
Antimicrobial agents are used in food production environments for treatment of infectious disease in food animals, for prevention of infectious disease (called prophylaxis) in food animals, and for the promotion of growth in food animals. Selection of bacterial variants which are resistant to one or more antimicrobial agents may be transmitted to other individuals.
Furthermore, bacteria have developed means to transfer their genes encoding antimicrobial resistance mechanisms to other bacteria. These DNA transfers between unrelated bacterial species may readily occur in the animal gut, where thousands, if not millions, of bacterial species are thought to reside.
2) Now, what exactly are food-borne pathogens?
Food-borne pathogens are microbes that are agents of infectious disease and intoxication (i.e., food-poisoning) and which are passed onto humans by contaminated foods or foods that are poorly cooked or improperly prepared. Such illnesses due to food-borne pathogens range from mild to relatively serious, depending on the nature of the microbe and the susceptibility of the human host. Food-borne pathogens may be serious concerns worldwide, especially in areas where living conditions or sanitation are chronically poor.
3) I think that we all know that overuse of antibiotics has resulted in some serious consequences. What are some of these consequences?
Examples of overuse and misuse of antibiotics include 1) not fully completing the course of treatment for bacterial infectious disease as prescribed by the physician and 2) using antibiotics for infections caused by viruses, as antibiotics are not effective against viruses. In both human clinical and agricultural settings, use of antimicrobial agents, such as antibiotics, has led to the selection of bacterial variants which are resistant to the antibiotics used. One consequence is that the selected bacterial variants are frequently also resistant to multiple antibiotics.
Another consequence is that the resistant and multiple-antibiotic resistant bacteria transfer their DNA harboring resistance genes to different species of bacteria. These resistant bacteria may transfer to others by person-to-person transmission and by food-borne modes of transmission. These multi-antibiotic resistant bacteria are becoming increasingly difficult to treat when they are causative agents of infectious disease in humans, especially in patients who are young, elderly or immune-compromised.
4) It was a while ago, but I recall studying Salmonella, Campylobacter, and Staphylococcus aureus, and Escherichia in some undergraduate science classes. But for our readership, can you describe each of these and why they are important?
Each of these bacteria may cause infectious disease, depending on the nature of the microbe and the circumstances of their interactions with humans. The bacterium, Salmonella enterica, is the causative agent of salmonellosis, such as typhoid fever, gastroenteritis and septicemia. This bacterium has been historically notorious, as typhoid fever has been included in the classic literature, like Great Expectations, by Charles Dickens. Additionally, S. enterica was responsible for the death of Louis Pasteur’s daughter, Cecile, in 1866 at the age of 12 years, from the typhoid fever.
The bacterium Campylobacter jejuni is a serious causative agent of acute gastroenteritis, especially where sewage contamination occurs, like that seen in floods. The Staphylococcus aureus bacterium has several variants which are methicillin-resistant (MRSA) and vancomycin-resistant (VRSA). These bacteria have been serious causes of healthcare facility- (HASA) and community-acquired (CASA) S. aureus infectious disease, because of their multidrug resistant natures.
The well-known and intensely studied Escherichia coli, on the other hand, is actually harmless as it resides in the gut of all animals, including all humans; these E. coli are used for basic research, like gene-cloning, for genomics, physiology, and biochemistry, for instance. The presence of E. coli anywhere outside of the laboratory, however, is an indicator of fecal contamination. There are, however, a handful of E. coli variants that are quite serious in their pathogenesis. These E. coli variants have wreaked havoc in human populations for many decades. One infamous E. coli pathogen, called strain O157:H7, was responsible for the so-called “Jack in the Box” outbreak involving contaminated beef and hundreds of deaths.
5) Some countries have banned the use of antibiotic growth promoters. Why is this important?
Due to the accumulated wealth of published data in peer-reviewed journals definitively documenting the association between the use of antimicrobial agents in agriculture and the development of transferable multidrug resistance genetic elements in bacteria, several antimicrobial agents have been banned in agriculture, especially in Europe, but also to a lesser extent in the U.S. The bans have resulted in no serious consequence to food production efficiency and to decreases in the incidence of certain resistant bacterial pathogens. The issue remains controversial, however, as consultants and officials from pharmaceutical companies are concerned about revenue and antimicrobial agent sales to the agriculture industry.
6) Now what exactly is an antimicrobial? And why are they important?
Antimicrobials are agents that kill and inhibit the growth of microbes. They are important for controlling microbes so that they do not result in contamination or incur infectious disease.
There are two general types of antimicrobials. The first type is physical in nature and includes agents such as heat and radiation, like X-rays or gamma radiation. The second type is chemical in nature, and includes agents which may be used for disinfection of inanimate surfaces, antisepsis of living tissue, or chemotherapeutically, such as with an antibiotic prescription for the treatment of a bacterial infection.
7) Now, what exactly do you mean by "human pathogens" or animal origin? And are there specific animals of concern?
By “human pathogen” we mean microbes that cause morbidity (disease) and mortality (death) in humans. Such microbes are pathogenic to humans. The term pathogenesis refers to the generation of disease. With respect to animals, there is concern that they (animals) may transmit microbial infections to humans.
Such microbial infections that are transmitted from animals to humans are referred to as zoonoses. Probably the animals of most concern involve those who have the most contact with humans. Interestingly, animals with little or no contact with humans obviously do not constitute a danger of infectious disease transmission. In cases of environmental encroachment and disruption by humans or by climate change, however, the chances of encountering these remote animals may be enhanced. The consequences of these interactions remain to be seen.
8) Why do we need a concerted global effort to minimize the use of antimicrobials?
It is widely believed by expert investigators in the field that minimization of antimicrobial use will foster conditions that thwart or circumvent the emergence of drug- and multidrug-resistant bacteria. If such were to be the case, then it is thought that clinically relevant antimicrobial agents that have been compromised by drug- and multi-drug resistant bacterial pathogens may once again be effective for treatment.
Such antimicrobial minimization might include using antibiotics only for clinical bacterial disease and finishing the entire course of antibiotic treatment for bacterial infections. Such programs of antimicrobial stewardship and prudent use of antimicrobials are ongoing and gaining a foothold, especially in clinical settings.
9) Where was your article published, and what have I neglected to ask?
Our peer-reviewed review article was accepted for publication in the scientific journal called Microorganisms and published March 14, 2017. The review briefly summarizes the history of antimicrobials, the various mechanisms of bacterial resistance to antimicrobials, the uses of antimicrobials in agriculture, the emergences and development of bacterial resistance in food production environments, and the efforts being performed in order to reduce conditions that foster emergence and spread of antimicrobial resistance. The review article is available online:
Abstract: http://www.mdpi.com/2076-2607/5/1/11/
PDF Version: http://www.mdpi.com/2076-2607/5/1/11/pdf
Title: The Food Production Environment and the Development of Antimicrobial Resistance in Human Pathogens of Animal Origin
Abstract: Food-borne pathogens are a serious human health concern worldwide, and the emergence of antibiotic resistant food pathogens has further confounded this problem. Once highly efficacious antibiotics are gradually becoming ineffective against many important pathogens resulting in severe treatment crises. Among several reasons for the development and spread of antimicrobial resistance, their overuse in animal food production systems for purposes other than treatment of infections is prominent. Many pathogens of animals are zoonotic, and therefore any development of resistance in pathogens associated with food animals can spread to humans through the food chain. Human infections by antibiotic resistant pathogens such as Campylobacter spp., Salmonella spp., Escherichia coli and Staphylococcus aureus are increasing. Considering the human health risk due to emerging antibiotic resistance in food animal-associated bacteria, many countries have banned the use of antibiotic growth promoters and the application in animals of antibiotics critically important in human medicine. Concerted global efforts are necessary to minimize the use of antimicrobials in food animals in order to control the development of antibiotic resistance in these systems and their spread to humans via food and water.