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Evolution of environmental microbial population in the emergence and global spread of antibiotic resistance

S. Kaushik and K. Padma
Department of Microbiology,
Dr.ALM PGIBMS,
University of Madras, Taramani Campus, Chennai- 600 113.
Email: padma.abpkn@gmail.com


Abstract

Antibiotic resistance has become a major public health issue for today’s human being. Globally, antibiotic resistance affects more people than the deadly diseases like HIV-AIDS. Environmental microbiota play a major role in the origin and spread of antibiotic resistance. The role of environmental microbiota in antibiotic resistance is not well acknowledged. Therefore, this paper documents the role of environmental microbes in the emergence and global spread of antibiotic resistance.

Introduction

     Bacteria were the first form of life to appear on earth, about 3.5 billion years ago and as a consequence they have acquired and learned the essentials of survival. From a Darwinian perspective, this ability to survive forms the basis for a successful evolution. This in turn facilitates their survival in the harshest of environments on earth.

Antibacterial therapy has emerged over the last 70 years and become the mainstay of treatment in modern medicine. Despite this, we have seen the development of antibiotic resistance even in the early 20th century when penicillin was discovered by Alexander Fleming. The refinements of antibiotic resistance is yet to be fully deciphered, one of the main reasons for this is the high level of complexity involved with antibiotic resistance both from a genetic and ecological perspective (Sykes, 2009).

The evolution of antibiotic resistance provides an ideal example of the latin term “ex unibus plurum (towards diversification) and ex pluribus unum (towards unification)” as many of the evolutionary units of antibiotic resistance have oscillatory dynamics. This further complicates our understanding of antibiotic resistance (Baquero, 2011).

Thus, antibiotic resistance is not only the consequence of genetic variation, but also a cause of such genetic variation. What we detect as molecular observers of antibiotic resistance are correlated changes in the frequency in entities as resistance
genes, other genes, plasmids, clones, species or bacterial
communities (Sykes, 2009).

In recent years, antibiotic resistance genes and the carriers of the resistant genes from non-clinical environment have gained more attention. It is largely due to the “butterfly effect” of rare genetic events, that are hypothesised to have occurred in the non clinical environment.

It is further substantiated by a current school of thought which states that antimicrobial-resistance genes and their genetic vectors, once evolved in bacteria of any kind, anywhere, can spread indirectly through the world’s interconnecting commensal, environmental, and pathogenic bacterial populations to other kinds of bacteria elsewhere.

Survival of the best connected

An emerging concept increasingly used in Public Health Microbiology is ‘high risk clones or clonal complexes’, referring to highly specialised genetic populations with enhanced ability to colonize, spread and persist in particular niches after acquiring adaptive characters including antibiotic resistance and replacing the antibiotic susceptible population. High connectivity promotes rapid Horizontal Gene Transfer (HGT). If a bacterium belongs to a preferential genetic exchange community, the probability of further evolution by HGT increases. This holds true, particularly for antibiotic resistant traits as it leads to rapid dissemination of genes (Baquero and Coque, 2011).

Genetic carriers of resistant genes

The carriers of antibiotic resistance consist of a complex system of genetic entities which are embedded within genetic elements of larger scale complexity. The overall picture is more complicated not only because of the number of elements involved, but also due to the heterogeneity of such components and their hierarchical organization.

Resistance genes are most often encoded in extrachromosomal genetic elements or in segments that appear to have been recombined into the chromosome from other genomes. The largest of the extra-chromosomal elements are the plasmids, which are self-replicating, double-stranded helices of DNA, some of which are involved in the transfer of the plasmid to another bacterial cell. Bacteria isolated from patients, about 70 years ago or more, before antimicrobials were first used, had plasmids similar to those seen now, but, then, the plasmids had no resistance genes. This indicates that plasmids are a subunit of bacterial evolution. Further, recent studies analyzing a few sequenced plasmids indicates that they contain an assortment of genetic elements with G+C content indicative of a wide array of living organisms including bacteriophages and environmental bacteria (Bonnet, 2004).

Resistance genes encoded in plasmids are often located within the segments, called transposons. Functioning transposons, include transposases, that enable the transposon to recombine into other genomes. Resistance genes are often further clustered within the elements called integrons, which are frequently found within transposons and plasmids, but also found in bacterial chromosomes. Each resistance gene in an integron is encoded in a mobile gene cassette that can be excised and then incorporated into another integron on another genome (O’Brien, 2002).

Antibiotic resistance and environmental bacteria

Although use of antibiotics for treating bacterial infection was a human intervention, antibiotics were an adaptation by the environmental bacteria to give them a competitive edge. In the game of one-upmanship, to occupy a particular ecological niche, environmental bacteria produce the antibiotic and the resistance mechanism to counter it. The wide array of above-mentioned genetic carriers mobilise the genes responsible for antibiotic resistance into the clinical environment. This is analogous to using civilian nuclear supplies for military operations. This is one facet of the overall scheme (Toleman and Walsh, 2011).

Environmental bacteria as a reservoir of clinically relevant resistant genes

Environmental bacteria are proven potential reservoir of clinically resistant genes, however direct evidence has been provided only for a few resistant genes in gram-negative bacteria. Important and significant among the environmental bacteria are the Kluyvera spp., a soil environmental bacteria of the family Enterobacteriaceae, which is considered as a reservoir of the CTX M gene family that encodes resistance to 3rd generation cephalosporins and Shewenella algae, a marine bacterium, is the reservoir of a quinolone resistance gene, qnr A. The mobilization of the genes from environmental bacteria to clinical pathogens is incremental in nature. It was catalysed by a few one off events (Toleman and Walsh, 2011).


Hierarchical organization of various genetic elements

Rare genetic one-off events in gram negative bacteria

There are three key one-off events that are at the heart event of current HGT of resistance genes in Gram-negative bacteria and ultimately necessary for the construction of large extended resistance islands such as (1) capture of the class 1 integrase gene and the attI1 site by the ancestor of the Tn5090/Tn402 transposon; (2) the formation of the 3‘ conserved segment (3‘-CS) by the fusion of the disinfectant resistance gene cassette qacE to a gene conferring sulphonamide resistance sul1 forming the fused genes qacEΔsul1 and (3) fusion of ISCR1 to the class 1 integron via qacEΔsul1 (Toleman and Walsh,2011).

All these events represent genetic recombination that occurs randomly. Only those that confer a selective advantage are maintained successfully which gives scope for further evolution. Though it is not possible to determine the exact time and place of the genetic recombination, it is possible to hypothecate only based on continuous observations. For instance, the transposon Tn 402 is a mercury resistant transposon which was used as antiseptic in the late 19th century. Further the qac E gene codes for quaternary ammonium compound resistance which was used as antiseptic in the early 20th century. The sul 1 gene fusion is believed to have occurred in the beginning of the antibiotic era because of the selective advantage that is conferred by deactivating sulphonamides, which were the first antimicrobials used. Further, the recently identified gene cassettes encode resistance to newer classes of antibiotics which indicates the emergence of class 1 integrons.


Structure of Class 1 Integron

Integrons and Environmental bacteria

Among the different mechanisms involved in lateral genetic transfer, the class 1 integrons are one of the most successful elements in the acquisition, abundance, maintenance and spread of antimicrobial resistance gene cassettes among gram-negative bacilli. Class 1 integrons are considered to be a molecular fossil to study the chronological evolutionary events in the development of antibiotic resistance because of their basic structure (Nardelli et al., 2012 ).

Overall, it is assumed that 2.65% of eubacterial cells in non-clinical samples contain a class 1 integron. However, factors involved in the distribution of non-clinical class 1 integrons within natural communities remain largely unknown. What is known with certainty is that the class 1 integrons confer a benefit to the host cell due to their ability to acquire gene cassettes that could provide advantages for survival in hostile environments. Hence, integrons are considered to be a surrogate marker of multiple antibiotic resistant traits which get disseminated via HGT.

A recent pilot study conducted on the drinking and seepage water samples in and around Chennai (unpublished data), indicated a low prevalence of class 1 integrons among cultivable environmental bacteria. Further, 6/7 class 1 integrons possessed novel 3‘ conserved segment indicative of further genetic recombination events in the non-clinical environment.

Since cultivable bacteria form a minor part of the non clinical environmental samples including water samples, metagenomic approach might reveal a true picture about antibiotic resistance and the non clinical environment.

Conclusion

Research focusing on the role of non-clinical environment needs to be carried out to know the role of these environments in the emergence and spread of antibiotic resistance which would give an understanding and pave the path for future therapeutic interventions based on ecology and evolution.

References

Baquero, F. (2011). Garrod’s lecture. The dimensions of evolution in antibiotic resistance. J. Antimicrob. Chemother. 66: PP:1659–1672.

Baquero, F. and Coque, T.M. (2011). Multilevel population genetics in antibiotic resistance. FEMS Microbiol. Rev. 35(5), pp: 705 – 706.

Bonnet, R. (2004). Antimicrobial agents and chemotherapy, Growing Group of Extended-Spectrum β-Lactamases: The CTX-M Enzymes. p. 1–14.

Nardelli, M., Scalzo, P.M., Ramı´rez, M.S., Quiroga, M.P., Cassini, M.H. and Centro´n, D. (2012). Class 1 Integrons in Environments with Different Degrees of Urbanization. PLOS one. 7(6). e39223.

O’Brien, T.F. (2002). Emergence, spread and environmental effect of antimicrobial resistance: How use of an antimicrobial anywhere can increase resistance to any antimicrobial anywhere else. Clin. Infect. Dis., 34(Suppl 3):S78-84.

Sykes, S.R. (2009). Garrod’s Lecture. J Antimicrob Chemother 2010; The evolution of antimicrobial resistance: A Darwinian perspective. 65: 1842–1852.

Toleman, M.A. and Walsh, T.R. (2011). Combinatorial events of insertion sequences and ICE in Gram-negative bacteria. FEMS Microbiol. Rev. 35(5). pp: 912 - 935

ENVIS CENTRE Newsletter Vol.12,Issue 1 Jan. - Mar 2014 Back 
 
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