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Antibiotics are substances given in a controlled amount, meant to kill or reduce the growth of microorganisms, particularly bacteria (Ghosh et al., 2007). These are usually naturally occurring substances and are mostly produced by microorganisms containing genes encoding resistance to different antibiotics they produce (Salyers et al., 1997). Besides their major applications in humans, these are used extensively in agriculture to increase crop productivity, in animal husbandry and livestock to treat sick animals, for prophylactic/metaphylactic purposes to prevent infections, and also as growth promoters in animal feed at controlled concentrations. When we look at the global consumption of various antibiotics, it has been reportedly found that approximately half of the antibiotics used in the entire animal husbandry are consumed in China, followed by US, Brazil, India and Germany (Laxminarayan et al., 2015). For livestock as well, it has been reported that in 2010, the largest antimicrobial consumer was China which was estimated to use up to 30% of the overall antimicrobial production globally; and at the current usage rate, India comes after China in the consumption of antimicrobials for livestock production and maintenance (Kleina et al., 2018). In 2015, among the developed countries, the leading consumers of antibiotics were USA, France, and Italy; and among the developing countries, India, China, and Pakistan topped the list where a 65% increase in consumption between 2000 and 2015 was reported globally (Ganguly et al., 2011). A study has also projected a 67% rise in antibiotic consumption by 2030 in various highly populated countries of the world including India (Van Boeckel et al., 2015). This extensive usage of antibiotics, although has resulted in the realization of an ever increasing demand of diverse agricultural and animal products; but their long-term application even at sub-therapeutic concentrations, directly on the fields or indirectly via animal manure, is adversely affecting the microbiota of agricultural soils.

Because of this overuse of antibiotics, the present century has also witnessed an extensive increase in the emergence of microbes which have been observed to modify their genes more rapidly and efficiently; helping them in developing resistance against different antibiotic groups, especially broad- spectrum antibiotics. Even the new generation antibiotics are reported to be inefficacious against such microbes, making this a major challenge for researchers to handle, and hence generating the need to find new methods to conquer this ever-rising issue. Development of new strategies to slowdown, or to provide an alternate solution to this emerging problem of multiple drug resistance is thus the need of the hour.

The present article is therefore aimed at shedding light on various problems generated globally due to an overuse of different types of antibiotics commonly used in agriculture and livestock; the rapid development of resistance by several bacteria against most of these commonly used antibiotics in agriculture; and some of the methods which are being researched upon to provide an alternate to antibiotics to overcome this major global issue. There is a dire need for the development of new alternatives to antibiotics, so that we are not only able to cure the existing diseases, but also because we need to become competent to prevent the initiation of new infections in the world.

2. Antibiotic consumption and development of antibiotic resistance in agriculture

 

Antibiotics are widely used in agriculture, livestock, poultry, fisheries and animal husbandry. In agriculture, antibiotics are most commonly used to prevent and cure various diseases in crops; whereas, in livestock and animal husbandry, these are most commonly used as growth promoting agents, and in preventing/ curing infections. There are at least 30 different antibiotics that are commonly used in agriculture and livestock, among which macrolides, penicillins and tetracyclines are the major ones (Laxminarayan et al., 2015) (Table 1). In animal husbandry alone, the average yearly consumption of antibiotics has been estimated as 172 mg/kg in pigs, 148 mg/kg in chicken, and 45 mg/kg in cattle worldwide (Van Boeckel et al., 2015).

Table 1. Antibiotics used in agriculture and animal husbandry.
 

 

Looking at the historical perspective of antibiotics usage in agriculture, streptomycin, an aminoglycoside, has been most commonly used in plant agriculture to treat diseases such as fire blight since early 1940’s. Till late 1940’s, due to a lack of effective bactericide alternatives for various plant diseases, there had been a decade-long dependence on streptomycin, thus resulting into an emergence of resistant strains against this antibiotic, and impeding the control of many diseases (Magnet et al., 2005, Mingoet et al., 1999). Various bacterial strains like Pseudomonas spp., and Xanthomonas campestris had been found to develop resistance against this antibiotic (Mac Manus et al., 1997). As a solution to this, amikacin, another aminoglycoside when introduced in late 1940s, was started being given in combination with other antibiotics. However, later on due to the resistance caused by aminoglycoside modification enzymes, other forms of aminoglycosides had to be proposed (Ramirez and Tomasky et al., 2017). Another class of antibiotics which came to be commonly used in 1950’s was tetracyclines. They were used for improvement in swine production and cattle production against both Gram-positive and Gram-negative bacteria, and for the control of other classes of micro-organisms such as eukaryotic protozoan parasites as well Roberts (2019). However, Shigella dysenteriae which causes bacterial dysentery first showed tetracycline resistance in the year 1953 Roberts (1996). Since then, mutations found in copious amount in various bacteria such as E.coli, Enterococcus, Staphylococcus, Streptococcus etc. were observed to cause resistance against tetracycline (Roberts, 1996, Cadena et al., 2018, Roberts, 2019). Methicillin, a β-lactam antibiotic acts by inhibiting penicillin-binding proteins (PBPs) that are involved in the synthesis of peptidoglycan layer surrounding the cell Stapleon and Taylor (2002). However, methicillin resistant Staphylococcus aureus (MRSA) also emerged soon, these were first isolated in the year 1961 in England and were initially found to be resistant against only β-lactam antibiotics (Brown and Reynolds, 1980). But with, the outbreak of MRSA, the prevalence of antibiotic resistance spread extensively during the 1980s, resulting into vancomycin becoming a more important drug as compared to penicillin, since it came into a wider use for the treatment of Gram-positive bacterial infections. Vancomycin was the antibiotic of choice until 2003 in treating MRSA infections, but since resistance to this agent also has rapidly developed recently, it has now become the drug of last resort for the treatment of MRSA (Swartz, 1994). Studies have also been conducted in which sulfonamide (sul) resistance in Psychrobacter, Enterococcus, and Bacillus sp. were reported for the first time in the year 2009. More recently, resistance has also been observed against fluoroquinolone, especially ciprofloxacin (CIP) which is used as a common treatment for Campylobacter caused gastroenteritis (Piddock, 1998). Further, a study proved the presence of erythromycin and other macrolide traces in livestock products such as liver, muscle, egg and milk (Petz et al., 1987).

The resistance was not only limited to animals and their products but was soon observed in agricultural soils. In one such study, Popowska et al. analyzed soils from agricultural fields and detected several genes (erm(C), erm(V), erm(X), msr(A), ole(B) and vga) responsible for erythromycin resistance in those soil samples (Popowska et al., 1987). Diverse, potentially mobile and abundant Antibiotic Resistance Genes (ARGs) of sulfonamides discovered in farm samples recommended that unchecked use of antibiotics was causing the emergence and release of ARGs in to the environment (Byrne et al., 2009). As a further confirmation of this fact, it has been observed that bacteria such as Citrobacter species, Enterobacter species, K. pneumonia, K. oxytoca, S. aureus, Proteus species and Y. enterocolitica have been found resistant to cephalosporins. Although, cephalosporin use is very restricted in food animals as compared to its use in humans, still resistance is being observed in various bacteria; this can only be explained by hypothesizing that the resistance is being transmitted from different environments to animals and then to humans (Wonhee et al., 2014). However, fifth generation cephalosporins are still in use.

In order to reduce the usage of antibiotics, and to generate a more effective method for disease resistance in crops, one of the strategies that humans have invented is the usage of genetically modified crops/transgenic crops. Transgenic crops are the ones in which insertion/deletion/silencing of the gene of interest is done in order to produce plants having desired qualities (Grifths et al. 2005). Insect resistant transgenic crops have also been introduced to save plants from insects and the pathogens that they carry on their body surface. Although, this helps minimize the economic burden on farmers by producing better crop yield, but recently, it has been observed that the resistance breakdown is increasing in target bacterial or insecticide population (Bawa and Anilakumar, 2013, Gilbert, 2013). Due to excessive cultivation of transgenic crops, high selection pressure is imparted on targeted insect population and weeds leading to evolution of new insect biotypes and emergence of superweeds posessing resistance against transgenic technology. Further, antibiotic resistance genes are also being transferred from the transgenic plants to the genome of non-target organisms such as non-transgenic crops and insects, for eg. Monarch butterfly feeding on milkweed leaves (Losey et al., 1999).

Thus, although transgenic crops were introduced as a means to reduce disease-resistance in crops, which in turn should have decreased the use of antibiotics and hence the spread of antibiotic resistance; but, on the contrary, the excessive cultivation of transgenic crops has today resulted indirectly into an increase in the spread of antibiotic resistance. Therefore, as demonstrated in all the above quoted studies, it can be concluded that due to an overuse of antibiotics, the resistance among various micro-organisms against the commonly used antibiotics (both in agriculture and in livestock) is increasing at a rapid pace; and through nutrient cycling, the genes responsible for this resistance are spreading rapidly among different environments.

 

Source: ScienceDirect