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Antibiotic Resistance – Counterattack by Salmonella

Karthik k Sophia I Rekha V Monika Bhardwaj Namrata Singh Ankita Jain
Vol 2(3), 42-47
DOI-

Antibiotics made its debut in 1940s which not only marked the start of antibiotic era but also the tragic era of antibiotic resistance. Darwin’s theory of “survival of fittest” is common to all known species on earth, why not it holds good for bacteria also. Most bacteria have evolved various ways and means to battle against the antibiotics. Salmonella is one of the smartest bacteria which is a common isolate from human and animals. It is so smart that its new variants show a greater degree of resilience against various groups of antibiotics. These new types are incorporated into the various recent outbreaks. Salmonella has various mechanisms to transport the resistance gene not only to other Salmonella but also to other bacteria. These resistance genes are carried either in the plasmid or in the chromosome. It’s high time that measures should be taken in order to tackle this major problem of antibiotic resistance to control dreadful diseases.


Keywords : Salmonella antibiotic resistance DT104

Introduction

Antibiotic resistance has become a day today used term, which can be termed as the ability of the microorganism to shield itself from the antimicrobial agents which are intended to terminate them. Antimicrobial resistance is an age old concept and not like a mushroom which shoots up within a day. Both antibiotics and the resistance to antibiotics go hand in hand. Bacteria are so clever that it finds new ways to battle the odds of antibacterial agents. Antibiotic resistance is the talk of the city because of the major health problems associated with the resistant strains. Antibiotic resistance has been recognized by World health organization (WHO) as an important public health problem [1] [2] [3].

Antibiotic Resistance-From a Vet’s Point Of View

Antibiotic resistance is a major concern for a veterinarian who treats the speechless patients. Two important areas of concern for a veterinarian are 1) the failure of treatment 2) resistance in zoonotic bacterial pathogen which can produce major impact in the community by jumping from animals to human and causing incurable diseases [1].

Antibiotics and Animal Husbandry

Antibiotic is a basic weapon in the armoury of a veterinarian to combat the microorganisms. These are commonly used in animal husbandry mainly for three purposes namely 1) therapy, 2) prophylaxis, 3) as a growth promoter. In all the three cases there are some bacteria which escape the attack and evolve into a new entity so that it becomes untouched by the same antibiotic which was previously showing its effect against those particular bacteria. Thus these resilient groups produce alarming effects in animal husbandry. Charles Darwin’s theory is well illustrated by S.typhi against ciprofloxacin [4].

Molecular Mechanism of Resistance

The antibiotics in use today act through different strategies namely cell wall synthesis inhibitors, protein synthesis inhibitors, DNA/RNA duplication and also by affecting biochemical process. But the bacteria have found new ways to counteract the mechanism of these antibiotics. Scientists over the decade tried to overcome this resistance by finding new ways. But now we are at a point of no return because knowledge about the physiology of bacterial cells has come to a halt. No new drugs have been to market after the last recognized antibiotic, fluoroquinolones [5].

Mechanism of Resistance – A Scientific Approach

Three major strategies are handled by bacteria in order to fight against antibiotic. The first of which is that it can destroy or modify the antibiotic so that it gets inactivated. β lactam group of antibiotics are destroyed by this strategy. β lactamase is the enzyme involved in this process. More than 80 β lactamase has been known today, of which TEM type and PSE type are common candidates of Salmonella [6]. Second approach is by blocking the access of antibiotic into the cell or to the target site. Sometimes the antibiotics are actively shipped out, common in tetracycline resistance [7]. The third mechanism is that the target site gets transformed, becoming inactive. Trimethoprim resistance [8] and fluoroquinolone resistance [9] [10] are the classic examples. The resistance mechanism in salmonella will be summarized in the upcoming headings.

Fluoroquinolones

Resistance to this group of antibiotic is due to the mutation in the quinolone resistance–determiningregion (QRDR) of the DNA gyrase genes, which is common in enterobacteriacea family [11]. Point mutation frequently occurs in the amino acids at codon 83. Next mechanism is the efflux pump mechanism.

Cephalosporins

Resistance to this group is the production of extended-spectrum cephalosporinases [12], [13]. Salmonellae reportedly produce a variety of such enzymes, highest of which are extended-spectrum beta -lactamases (ESBLs; particularly CTX-M types) and AmpC b-lactamases (particularly CMY-2 type) that can hydrolyze cephalosporins as well as cephamycins [14], [15],[16].

Resistance Gene Transfer

Resistance genes can be exchanged among bacteria and can be passed to mammalian cells also [17] [18]. This transfer can be of a single resistance gene transfer or a complex genetic material transfer as a whole. Individual resistance gene can be shipped by transformation or transduction. Transformation is the uptake of naked DNA by a cell, important in case of gram positive bacteria. Bacteriophages are viruses affecting bacteria which handle the transduction. Bacteriophages act as a vehicle by transporting the resistance gene to new host. Transduction is important in case of Salmonella because many strains carry prophage [19] [20].

Conjugation is the well established mode of resistance gene transfer in case of Salmonella. Conjugation can be stated as a parasexual process in which an extra chromosomal DNA, the plasmid snakes out from a donor to a recipient. Plasmids carrying resistance genes are called as R factors, which are grouped into incompatibility groups (Inc groups) i.e, two Inc groups cannot exist in a single cell [21].

Transposons are called as jumping genes which leaps within a DNA or between DNA and plasmid. These transposons are also involved in resistance gene transfer.

Strategies of Salmonella against Antibiotics

First report of resistant Salmonella dates back to 1960s [22] [23]. Experiments conducted by many scientists concluded that S.Typhimurium shows a very great resistance than other serovars [24]. S.Typhimurium phage type (PT) 29 became dominant in late 1960s in bovine infections [25]. PT29 was the first pentaresistant phage type which is resistant to tetracycline, ampicillin, neomycin, kanamycin and furozolidone. PT505 which is found during 1970s carried tetracycline resistance in the plasmid [26]. Apramycin was licensed in 1980s for veterinary use. Within a span of 4 years Salmonella has evolved strategies to combat against this drug. They produce the enzyme 3-N acetyl transferase IV [ACC (3) IV] and also carried conjugative plasmids [27].

S.dublin isolates have multiple drug resistance and show chromosomal integration of resistance gene [28]. Chromosomal integration is the talk of the hour and S.Typhimurium DT104 has a higher role in this. Current studies reviled that S. enterica Choleraesuis shows resistance to multidrugs [29]. Mostly they are 90% resistant to ampicillin, chloramphenicol, or sulfamethoxazole-trimethoprim, and ∼70% are resistant to ciprofloxacin [30], [31].

Properties of resistant Salmonella

S.wien has resistance against ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline, transferring it to cause epidemics from sporadic occurrence [32]. The resistant marker rests on the IncFImc plasmid [33] [34].

S.Typhimurium Phage Types

S.Typhimurium phage types DT193, DT204 and related phage DT204c are zoonotic. Cattle and calves act as a reservoir for this phage types. Through food chain they are transported to humans [35]. The phage type DT204c is a dominant phage showing high genetic flexibility, variability with the help of R factors, transposons and prophage [36].

S.Typhimurium DT104 is another candidate which is a common isolate of human and animal species. It is also a multidrug resistant candidate and the resistant gene resides on the chromosome. Hence the chance for losing the gene for resistance is lesser compared to the genes carried in the extra chromosomal elements.

Epidemiology of DT104

DT104 is also a pentaresistance phage type which is resistant against ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline. But today the resistance has also creped to gentamicin, trimethoprim and fluoroquinolone. Pentaresistant DT104 was first noticed in exotic birds which are now seen in cattle. From 1984 this has been isolated from human as well [37]. This DT104 was first unearthed in United Kingdom later it ducked into different parts of the world. Now it is around the globe and a major problem of concern.

DT104 did not spare any animal and it is seen in almost all livestock and also in some wild animals. Infection in cattle can be symptomless for almost half a year and later infection shoots up [38].

The major mode or route cause for the spread of DT104 to cattle has not come to limelight. The major factors suggested are herd management, hygiene, housing conditions, vector and lack of quarantine facilities [39].

Home of Resistance Gene in DT104

Resistance genes in DT104 reside in the chromosome of the bacteria [37]. Resistance for trimehtoprim is located on a mobilizable plasmid [40]. PCR analysis showed two integrons, which act as a cargo for the resistance gene. First integron carried resistance for aminoglycosides. β lactamase was seen on the second integron [41]. Fluoroquinolone is the recommended drug for life threatening Salmonella infections. But Salmonella become resistant to this drug also.

Steps to Keep Resistance under Control

Certain precautionary measures should be followed in order to overcome the problem of antibiotic resistance. Measures that can be followed include:

  1. If the infection is addressed earlier, resistance can be kept under control
  2. The organism which is the causative of the disease should be isolated first before beginning the treatment.
  3. Blind folded use of antibiotics should be discontinued.
  4. Lower generation antibiotics should be used first prior to the use of newer generation antibiotics [42]. Thus newer generation antibiotics can be reserved for mutated version the organism. [43].
  5. If possible therapy for individual animal can be performed with narrow spectrum drug.
  6. Dose and time of therapy should be followed correctly [44].
  7. Sales of over the counter drugs should be prohibited.
  8. Hygienic practices in the clinics can help to prevent the spread of resistant organism

Conclusion

The microbial world has shown remarkable ways to counterattack the antimicrobial agents. Salmonella being a common organism isolated from both animals and human is a good representative of what will happen in other bacterial organism, which might hit the animal and human hardly. Salmonella has played a key role in transferring the resistance gene within its own community and also to other bacterial community. By following basic principles the evolution of resistance can be blocked. Short gun therapy should be withheld in order to check the antibiotic resistance under control. Novel antibiotics should be invented in order to counteract these resistant variants. Lower generation antibiotics should be first followed by higher generation antibiotics in order to avoid the problem of antibiotic resistance.

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