While some human activities are slowing the spread of certain infectious diseases, some have promoted them. Advances in public sanitation, hygiene, and medicine have all helped to prevent the unnecessary suffering of illness. Effective vaccines and worldwide vaccination programs have severely reduced many types of adult and childhood infections such as mumps and measles, while smallpox and polio are rarities in most parts of the world. The rapid evolution of pathogens, however, may bring the biggest challenge of all, widespread antibiotic resistance.

The Challenges of Antimicrobial Resistance

According to WHO, Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses, and fungi: A post-antibiotic era in which common infections and minor injuries can kill far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century. [1]

Often, bacteria reproduce so quickly they are constantly spinning out new mutations from one generation to the next, mutations that will, typically, change how the cell wall is assembled. Penicillin, the world's most effective antibiotic, prevents one step in the bacterial cell wall synthesis.

Antibiotic resistance can develop very quickly when a bacterium has newly acquired or mutated specific genes that can synthesize new enzymes that will not bind penicillin, typically, a lag of only a year or two. Detecting such subtle changes to the genetic code of invading microbes requires either high-throughput PCR technology or long-chain DNA sequencing capability, which is often limited in clinical settings. Assessing the long-read genome as a whole structure provides a better and more unique snapshot of plasmid diversity that would not have been gleamed by analyzing single genes.

Recent research demonstrated by Conlan et al. applied long-read genome sequencing to identify plasmids harboring the gene blaKPc, which encodes for a carbapenemase that hydrolyzes carbapenem antibiotics [2]. An outbreak of Klebsiella pneumonia, a type of carapenem-resistant Enterobacteriaceae (CRE) in 2011 killed six infected patients, and prompted the NIH Clinical Center to carry out the study.

The incidence of CRE has quadrupled in the last decade in the United States, according to background information in the report. CRE has been detected in nearly 4 percent of hospitals and about 18 percent of long-term acute care facilities. In addition, the researchers noted, CRE are resistant to most, if not all, antibiotics. Investigations have reported a death rate of 40 to 80 percent from infection [3].

Given ongoing concerns that even bacteria like Klebsiella and Enterobacteria which are found in the environment and in healthy stomachs are becoming increasingly resistant to last-resort antibiotics, the researchers set out to find some answers. Over the course of two years, the researchers identified 10 patients seen at the U.S. National Institutes of Health Clinical Center who had resistance to carbapenems. Their report, published September 19th, 2014 in Science, showed that plasmid transfer in hospitals is likely contributing to the increase of antibiotic-resistance in bacteria.

Drug Resistance on The Move

Previous studies conducted in 2012, found antibiotic-resistant genes in tiny collections of organisms called biofilms living in hospital sink drains in patient rooms. This finding did not show that bacteria from the sink drain were passed to any patient, the study authors noted. But despite the fact that patients who were carried this bacteria may not have gotten sick themselves, they can pass this drug-resistance to others, they added [4].

Study co-author Julie Segre, chief and senior investigator at the U.S. National Human Genome Research Institute, noted, "We are trying to reinforce the message that these drug-resistant bacteria can't become so prevalent that we can no longer control them." And she emphasized, "We are still at the point where we can make a difference in terms of controlling the bacteria."

However, Palmore said, knowing how bacteria become drug-resistant doesn't necessarily change how preventing their spread is carried out.

"It informs us of how bacteria can pick up the resistance," Palmore said. "Efforts to control these bacteria need to focus on containing them by isolating patients who are carriers of the bacteria and also by disinfecting the hospital environment where the bacteria might live."

Plasmid DNA plays a key role in distributing anti-microbial genes within pathogenic bacteria, and can also help surveillance the transfer of genetic elements between bacteria, known as horizontal transfer. Their comparisons of the arrangement of its structure was only be revealed after closing the plasmid genome, known as long-read sequencing.

Short-read sequencing technologies may be able to affordably detect the mobile elements in genes, these horizontal insertion sequences, but is limited when it comes to determining a gene's precise location in the plasmid. By contrast, the gene sequences produced through long-chain sequencing (traditionally accomplished using the Sanger sequencing) offers a more complete picture with clear advantages since it places the genome into the whole context. Having such information will enhance our understanding of plasmid transfer, epidemiology, as well as bacterial evolution.

Only in the past few years has antibiotic resistance captured full attention of medical agencies and practitioners alike. Public awareness about this epidemic has led to a greater public outcry to eradicate this, as well. The problem we face is that antibiotic resistance is a growing plague difficult to predict and easy to overlook. We could throw all the time, money, and resources toward the next best drug, which will only be able to be, at best, a part of the solution. The most implacable foe is biology itself.

SOURCES

[1] WHO. Antimicrobial resistance: Global report on surveillance 2014. 2014.

[2] S. Conlan et al., Sci. Transl. Med. 2014. 254. 254r126.

[3,4] Evan S Snitkin, Adrian M Zelazny, Pamela J Thomas, Frida Stock, David K Henderson, Tara N Palmore, Julia A Segre. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing.Science Translational Medicine (2012).