Battling against resistance

25th March 2014
By Janina Dordel

Phylogenetic reconstruction of samples with inferred location and sexual orientation.

Phylogenetic reconstruction of samples with inferred location and sexual orientation.

A clear understanding of the evolution of bacteria is needed to impede the emergence and spread of resistant bacteria. As Maria Fookes explained in her recent blog, Know your Enemy, understanding the arsenal, the history and the relatedness of our bacterial enemies is crucial if we want to fight back. This knowledge is even more vital now that our molecular weapons are becoming depleted.

The discovery of antibiotics at the beginning of the 20th century is one of the biggest milestones in medical history and has saved many lives, making otherwise lethal bacterial infections treatable. However, bacterial strains soon started to defend themselves, developing resistance against antibiotics. Due to this growing resistance, together with the lack of new antimicrobial drugs, bacterial infections are becoming a worldwide threat once again.

One example of an organism that has recently raised fears about becoming untreatable is Neisseria gonorrhoeae – the cause of the sexually transmitted disease gonorrhea. This disease, while almost never lethal, can cause serious reproductive complications if it is not treated.

As is the case with many other bacteria, N. gonorrhoeae has acquired resistance to antibiotics used to treat it. In 2012, the United States Centers for Disease Control and Prevention (CDC) decided to no longer recommend the use of the oral antibiotic cefixime. The reason for this is that more and more N. gonorrhoeae isolates with reduced susceptibility to cefixime were found, making treatment with this drug less effective. By limiting the use of cefixime they hope to slow down the development of resistance against the whole family of antibiotics to which cefixime belongs (cephalosporins).

To get a better idea of the genetic basis of cefixime resistance and the way it emerges, we recently compared more than 200 N. gonorrhoeae genomes from the US. Of the examined samples, 50 per cent showed reduced susceptibility to cefixime, and 50 per cent were fully susceptible. Using the information from these whole genomes gives us very high-resolution insights into N. gonorrhoeae, which can be used to learn about its history and discover its weaknesses.

We showed that almost all samples with reduced susceptibility to cefixime had a specific gene in common (mosaic penA XXXIV), indicating that the presence of this gene could be used to predict reduced susceptibility against cefixime, at least in this population. This could be particularly useful in a clinical setting where the application of the right drug is crucial for the treatment success and treatment failure can fuel the emergence and spread of resistant bugs.

By inferring the evolutionary relationships among these isolates, we revealed that they form two distantly related groups. This indicates that resistance to cefixime didn’t emerge multiple times in multiple places in the US, but was spread through the US predominantly by two lineages.

Using information about the sexual orientation and the geographical origin of the infected people, we created a model to infer the route that one of the groups of N. gonorrhoeae appeared to take in spreading through the US: circulating first on the west coast and in Hawaii, they then spread eastwards through networks of men who have sex with men, with occasional introductions into the heterosexual population.

Using whole-genome sequencing to track transmission and dissemination as well as to explore and even stop outbreaks of infectious diseases caused by viruses and bacteria has been shown to be very effective. We believe that these newly developed methods and our findings will contribute to understanding the evolution and spread of antibiotic resistant N. gonorrhoeae and can help future public health initiatives to slow or contain the spread of resistant pathogens. Watch out, gonorrhea – we are fighting back!

This study was led by the Harvard School of Public Health and the Pathogen Genomics team at the Wellcome Trust Sanger Institute, in collaboration with the CDC and the Gonococcal Isolate Surveillance Project (GISP).

Janina Dordel is a Postdoctoral Fellow in the Pathogen Genomics group at the Wellcome Trust Sanger Institute.