Neisseria gonorrhoeae is a strict human pathogen that causes an estimated ninety-five million cases of gonorrhea worldwide each year. Without an effective vaccine, antibiotic therapy remains the principle mechanism to reduce or block the transmission of the gonococcus in the community. Unfortunately, because of the development of mutations or the acquisition of resistance determinants, the gonococcus has developed resistance to relatively inexpensive antibiotics and new strategies will be needed to counteract this problem. Gonorrhea is an ancient disease of mankind. Thus, it is not surprising that this strict human pathogen has evolved mechanisms to deal with antimicrobial threats. We have identified a novel mechanism used by gonococci to resist the host-derived antimicrobials (e.g., mediators of innate host defense) that mimic the action of classical antibiotics;this resistance involves the coating of gonococci with host-derived polyamines. We have found that biologically relevant concentrations of polyamines can also inhibit biofilm formation by gonococci. Using spermine as a model polyamine, we have acquired evidence that gonococci mount a stress response in its presence. In order to better understand how polyamines influence the pathogenic potential of gonococci during infection, we will define bacterial factors that are important in determining polyamine-mediated modulation of biofilm formation and dispersion, as well as the interaction of gonococci with host cells (Specific Aim 1). We will also determine the responses made by gonococci at the transcriptional and translational levels in the presence of physiologically relevant levels of spermine and will construct nonpolar mutations in spermine-responsive genes so as to better understand how this pathogen might use host polyamines to proliferate during infection (Specific Aim 2). The results obtained during the two-year funding should provide novel insights regarding how the gonococcus responds to compounds in its natural environment, which is important in the development of new therapeutic agents that block infection or eradicate gonococci at the genital mucosal surface of men and women.
The goal of this project is to understand how a family of host-derived compounds (polyamines) alters the capacity of Neisseria gonorrhoeae to form a biofilm, interact with host cells and resist antimicrobial systems that are relevant during infection. The information gained will advance our understanding of the pathogenic mechanisms employed by gonococci and help in the development of new antimicrobials to treat or prevent gonorrhea, which remains a worldwide public health problem.
|Shafer, William M (2016) Does the Cervicovaginal Microbiome Facilitate Transmission of Neisseria gonorrhoeae From Women to Men? Implications for Understanding Transmission of Gonorrhea and Advancing Vaccine Development. J Infect Dis 214:1615-1617|
|Djoko, Karrera Y; Goytia, Maira M; Donnelly, Paul S et al. (2015) Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics. Antimicrob Agents Chemother 59:6444-53|
|Unemo, Magnus; Shafer, William M (2015) Future treatment of gonorrhea--novel emerging drugs are essential and in progress? Expert Opin Emerg Drugs 20:357-60|
|Goytia, Maira; Hawel 3rd, Leo; Dhulipala, Vijaya L et al. (2015) Characterization of a spermine/spermidine transport system reveals a novel DNA sequence duplication in Neisseria gonorrhoeae. FEMS Microbiol Lett 362:|
|Unemo, Magnus; Shafer, William M (2014) Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 27:587-613|
|Goytia, Maira; Dhulipala, Vijaya L; Shafer, William M (2013) Spermine impairs biofilm formation by Neisseria gonorrhoeae. FEMS Microbiol Lett 343:64-9|