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Metal ion export in bacteria:
This project focuses on the structure, assembly and mechanism of the resistance-nodulation-cell division (RND)-superfamily efflux pumps.These efflux pumps are key components for Gram-negative pathogens to ensure their survival in toxic environments by extruding a variety of antimicrobial agents from bacterial cells. Typically, RND efflux pumps work in conjunction with a periplasmic membrane fusion protein and an outer membrane channel to form a functional protein complex. One such RND-type efflux system is the Escherichia coli CusCFBA tetrapartite heavy-metal efflux system, which specifically recognizes and confers resistance to Ag(I) and Cu(I) ions. Recently, our lab has determined the crystal structures of the CusA heavy-metal efflux pump. We have also resolved the crystal structure of the CusBA adaptor-transporter efflux complex. This is the only adaptor-transporter efflux complex structure that has been determined using X-ray crystallography. In addition, we have determined two mutant structures of the CusC efflux channel, reviewing conformational changes accompanying folding and transmembrane channel formation of this outer membrane protein.
The MtrCDE tripartite multidrug efflux system of Neisseria gonorrhoeae:
Neisseria gonorrhoeae is a successful strictly human pathogen, which causes the sexually transmitted infection (STI) gonorrhea. This STI is the second most commonly reported infection in the United States and more than 78 million cases occur annually worldwide.
Over the decades the gonococcus has developed resistance to a range of clinically relevant antibiotics, including beta-lactams, tetracyclines, macrolides and quinolones. Multidrug efflux is considered to be one of the major causes of failure of drug-based treatments of bacterial infections, which appear to be proliferating in prevalence. Therefore, we propose to target the N. gonorrhoeae MtrCDE (multiple transferable resistance) tripartite multidrug efflux system, which has been demonstrated to contribute to the resistance of both antibiotics and host-derived antimicrobials, forbidding this system to piece together and work properly. The MtrCDE tripartite efflux pump is composed of the MtrD inner membrane transporter, MtrC periplasmic membrane fusion protein and MtrE outer membrane channel. These three efflux proteins contact one another at the periplasmic space and assemble to form a powerful tripartite system, mediating resistance to a broad spectrum of antimicrobial agents and gonadal steroidal hormones. Recently, we have determined the crystal structures of the MtrD and MtrE membrane proteins. In collaboration with Dr. William Shafer of Emory University School of Medicine, we are currently rationally designing peptides that tightly attach to these efflux proteins at the PPIs, prohibiting them to unite and function.
Structure and mechanism of the AbgT-family transporters:
The main goal of this proposal is to elucidate the structures and fundamental mechanisms of the AbgT family of transporters. n particular, we will focus on delineating the structure and function of the Alcanivorax borkumensis YdaH and Neisseria gonorrhoeae MtrF inner membrane transporters. To date, approximately 13,000 putative transporters of the AbgT family have been identified. Surprisingly, among proteins in this diverse family, only E. coli AbgT and N. gonorrhoeae MtrF have been partially characterized. Thus far, there is no structural information available for this family of membrane proteins, obscuring the details of their function and mechanism. Recently, we have successfully determined the X-ray structures of the A. borkumensis YdaH and N. gonorrhoeae MtrF transporters. Our novel findings strongly suggest that both YdaH and MtrF behave as antibiotic efflux pumps, which are able to remove sulfonamides from the cell and effect bacterial resistance to this class of antimetabolites.
Drug Efflux and Transcriptional Regulation in Campylobacter jejuni:
Campylobacter jejuni is a major causative agent of human enterocolitis and is responsible for more than 400 million cases of diarrhea each year worldwide. Campylobacter infection may also trigger an autoimmune response, which is associated with the development of Guillain-Barre syndrome, an acute flaccid paralysis caused by degeneration of the peripheral nervous system. For antibiotic treatment of human campylobacteriosis, fluoroquinolones and macrolides are frequently prescribed. Unfortunately, Campylobacter has developed resistance to these antimicrobials, especially fluoroquinolones. According to the genomic sequence of NCTC 11168, C. jejuni harbors 13 putative antibiotic efflux transporters that mediate resistance to antimicrobial agents. Among them, the Campylobacter multidrug efflux system CmeABC is the primary antibiotic efflux system in C. jejuni. CmeABC consists of three components including an outer membrane protein (CmeC), an inner membrane drug transporter (CmeB), and a periplasmic membrane fusion protein (CmeA). We are currently collaborating with Dr. Qijing Zhang of ISU to understand how this multidrug efflux system works. We have already defined several crystal structures of these efflux proteins, including the CmeC outer membrane channel and CmeR transcriptional regulator.
Regulation of Cell Wall Biosynthesis in Mycobacterium tuberculosis:
Tuberculosis (TB) is one of the oldest described diseases and remains a significant global problem with more than eight million new cases reported annually.
The World Health Organization estimates that one-third of the world's population is infected with M. tuberculosis and most of these individuals have latent TB. The mycobacterial cell wall plays a key role in the host-pathogen interface since it is associated with the Mtb pathogenesis and provides a barrier against environmental stresses, antibiotics and the host immune response. Recent work demonstrated that the Mycobacterial membrane protein large (MmpL) proteins are cell wall lipid transporters that belong to the RND superfamily. The MmpL transporters are crucial contributors to mycobacterial physiology and pathogenesis.
There is strong evidence that these MmpL proteins are responsible for exporting fatty acids and lipidic elements of the cell wall. In collaboration with Dr. Georgiana Purdy, we have started exploring the regulation of MmpL protein expression and the role of MmpLs in cell wall remodeling in different environmental conditions. Our previous efforts have focused on elucidating how M. tuberculosis transport systems are regulated. Understanding the structure and function of these regulators are important to the field since they are involved in the way that Mtb senses physiological changes and adapts to the host environment.
Highlight of our research
- Iowa State, Ames Lab scientists describe protein pumps that allow bacteria to resist drugs
- Iowa State, Ames Lab researchers study the structure of drug resistance in tuberculosis
- Iowa State, Ames Lab researchers describe the pump that bacteria use to resist drugs
- Iowa State, Ames Lab researchers identify structure that allows bacteria to resist drugs