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Research Themes Drug discovery

Superbugs and Antibiotic Resistance

SBKB [doi:10.3942/psi_sgkb/fm_2011_12]
Featured System - December 2011
Short description: Antibiotics were used as weapons to fight bacteria long before Alexander Fleming discovered penicillin.

Antibiotics were used as weapons to fight bacteria long before Alexander Fleming discovered penicillin. Natural antibiotics like penicillin are made by fungi and other organisms to protect themselves, and as you might expect, bacteria have found many ways to avoid these protections. For instance, beta-lactamases, enzymes that break a key bond in penicillin, were discovered in antibiotic-resistant bacteria before penicillin was ever used in the clinic. However, our widespread use of antibiotics has escalated the battle, leading to the rise of "superbugs" that are resistant to most of the currently known antibiotics. The bacteria have a great advantage in this battle: they grow quickly, they are found in huge numbers, and they have many efficient methods to exchange genes with other resistant bacteria.

Anti-antibiotics

NDM-1 (New Delhi metallo-beta-lactamase, shown here from PDB entry 3sfp), is a recent development in this battle. It is an enzyme that destroys almost all known beta-lactam antibiotics, including familiar antibiotics like penicillin as well as specialized carbapenem antibiotics that were specifically designed to fight resistance. To make things worse, the gene for this enzyme is readily traded between bacteria in a plasmid that includes other anti-antibiotic weapons, including enzymes that break down other types of antibiotics like erythromycin and chloramphenicol and a special pump that ejects antibiotics out of bacterial cells.

Destroying Drugs

As with many other enzymes involved in antibiotic resistance, NDM-1 modifies antibiotics, rendering them ineffective. Some of these enzymes, such as APH(4)-Ia (shown here from PDB entry 3tyk) attach bulky groups like phosphates or nucleotides to the drug, making them too big to bind to their bacterial targets. Others, like NDM-1, break bonds in the antibiotic, destroying its ability to form a covalent bond to the target. NDM-1 uses two zinc ions in its cleavage reaction, that activate a water molecule and stabilize an intermediate form of the antibiotic, making sure that the reaction proceeds smoothly. NDM-1 is also surprisingly effective against many different antibiotics. Structures of NDM-1 from the PSI give an explanation: the active site is much larger than the active sites of similar enzymes. Also, by solving many structures in slightly different states, they have observed that the enzyme is quite flexible, which may be important for accommodating targets of different sizes and shapes.

A Continuing Battle

Of course, researchers are fighting back and devising new ways to block bacterial resistance. Because of its critical importance in this battle, NDM-1 was chosen as a target by the PSI Biology Partnership MBTI and the structure was solved by their high-throughput partner MCSG. As with all PSI structures, the atomic coordinates are released quickly, providing the information needed to design new compounds to block its action. This would allow a two-pronged treatment that would include a traditional beta-lactam antibiotic to block cell wall synthesis and ultimately kill the bacteria, along with a second drug to thwart NDM-1 and protect the antibiotic. The structure of NDM-1 reveals the details of the active site, including the location of the catalytic zinc ions and a flexible loop that may be involved in the ability of the enzyme to attach a wide variety of drugs. To take a closer look at these structures, the JSmol tab below displays an interactive JSmol.

Bacterial E3 Ubiquitin Ligases

Structures of the two domains of bacterial E3 ubiquitin ligases are included in this Jmol: the protein-targetting domain of Salmonella SlrP, and the catalytic domain of Shigella IpaH. Use the buttons to look at the two structures and to change the representation. A key cysteine amino acid is thought to be essential for the ubiquitin-transfer reaction--it is shown in bright yellow spheres in the catalytic domain structure.

References

  1. Kim, Y. et al. Structure of apo- and monometalated forms of NDM-1 - a highly potent carbapenem-hydrolyzing metallo-beta-lactamase. PLoS One 6, e24621 (2011).

  2. Stogios, P. J. et al. Structure and function of APH(4)-Ia, a hygromycin B resistance enzyme. J. Biol. Chem. 286, 1966-1975 (2011).

  3. Moellering, R. C. NDM-1 - a cause for worldwide concern. New Engl. J. Med. 363, 2377-2379 (2010).

  4. Singer, A. U. et al. Structure of the Shigella T3SS effector IpaH defines a new class of E3 ubiquitin ligases. Nature Struct. Mol. Biol. 15, 1293-1301 (2008).

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