UF Emerging Pathogens Institute researchers make seminal discovery in antibiotic resistance

UF Emerging Pathogens Institute researchers make seminal discovery in antibiotic resistance
Pictured from left are Drs. Apichai Tuanyok, Sunisa Chirakul, Nawarat Somprasong, Michael Norris and Herbert Schweizer.

Burkholderia pseudomallei is a bacterium that is found in soil and water in tropical and subtropical regions of the world, including Central and South America and the Caribbean Islands. It is an emerging pathogen that causes meliodosis, an underdiagnosed disease with high morbidity and mortality that is resilient to antibiotic treatment. Outside of highly endemic regions the bacterium did not receive much attention until its designation as potential biothreat agent in the early 21st century. Anecdotally, the malicious use of the bacterium as the cause of the fictional infectious disease Tapanuli fever was plotted nearly a century earlier in the Sherlock Holmes’ The Adventure of the Dying Detective story published in 1913, after the first recognition of what was then called Bacillus pseudomallei in 1911 in Burma (now Myanmar).  

In previous work the research team led by Dr. Herbert Schweizer of the UF School of Medicine Department of Molecular Genetics & Microbiology and Emerging Pathogens Institute showed that B. pseudomallei uses unique mechanisms to resist antibiotics. 

Dr. Sunisa Chirakul holds a Petri dish in front of her lab bench. She is a postdoc in Dr. Schweizer's lab.

Antibiotic resistance is currently causing a worsening global health crisis. The global, regional and local spread of antibiotic resistance is accelerated by the ready transfer of resistance genes between different bacteria on mobile elements. A surprise finding in B. pseudomallei is that the organism does not naturally acquire resistance genes from other bacteria via this route. Over the last decade research in Schweizer’s laboratory showed that in the absence of externally acquired resistance factors the bacterium exploits and co-opts intrinsically present resistance genes. The clinically most relevant case is the enzyme PenA ß-lactamase that is naturally present in B. pseudomallei. This enzyme inactivates penicillin antibiotics that are staple drugs for treatment of infections caused by this bacterium. Dr. Schweizer’s team and others previously showed that changes in PenA ß-lactamase expression and modification render most penicillin antibiotics unusable with this bacterium, including the widely employed ceftazidime. The focus of studies described in a recently published article was on solving the mystery of how the expression of PenA was regulated and how mutational events cause deregulation, and thus enzyme overexpression and resistance.

To resolve the mystery, Dr. Schweizer’s team collaborated with his UF Burkholderia research group colleague Dr. Apichai Tuanyok, Dr. Brad Borlee at Colorado State University and Dr. Olga Lomovskaya at The Medicines Company, a biotech company involved in antibacterial discovery. A molecular examination of the genetic environment in which the PenA ß-lactamase gene is located on the genome revealed a unique gene organization and associated regulatory elements. The key finding was that a conserved single nucleotide mutation that is present in ceftazidime resistant but absent from susceptible clinical B. pseudomallei isolates plays a pivotal role in ß-lactamase gene expression. Its presence and position negates the effects of a transcriptional terminator and results in increased transcription of the PenA ß-lactamase gene, which in turn causes resistance to clinically useful ß-lactamase antibiotics.

Dr. Michael Norris and Dr. Herbert Schweizer standing in the BSL 2 lab. 

Dr. Schweizer emphasizes that this study has important implications in the identification of resistance mechanisms for purposes of informing proper therapy of bacterial infections. Currently used diagnostic methods are largely focused on detecting the presence or absence of genes that code for resistance determinants. However, the present work clearly shows that such an approach is misguided in bacteria that employ mutational changes in resistance determinant expression and modification. Detection of such changes requires new diagnostic paradigms and methods, and the knowledge gained from studies such as this is indispensable for their implementation.

The article describing this work was published in Scientific Reports and can be found here.