Azithromycin (Zithromax, or Z-Pak)

So today was our last day of orgo lab, and we all presented on our drug synthesis papers. In my paper and in my presentation today, I explained the synthesis and biochemical function of azithromycin, also known as Zithromax or Z-Pak. This molecule is a 15-membered macrolide antibiotic. A macrolide antibiotic is a molecule/drug containinga macrocylic lactone ring and 2 attached sugars. Macrolide antibiotics come in many shapes and sizes, but what is unique about azithromycin is its extended half-life compared to other macrolides. While most other macrolides have either 13 or 14 membered macrocyclic lactone rings, azithromycin has a 15 membered ring. This difference, and several other differences, allow for azithromycin to have about a 11-14 hour half-life, compared to say, erythromycin A, a 14-membered macrolide, that has about a 6 hour half-life. Because of this long half-life, azithromycin is actually in a much higher concentration in your macrophages/tissues than other antibiotics when you take it, which allows doctors to be able to prescribe it over a much shorter amount of time than other antibiotics, usually only  for 5 days. (Some antibiotics have to be taken for 21 days to complete their effect!) Some causes for concern lately, however, involve studies that show that azithromycin may actually increase the QT interval during heart muscle depolarization. Basically, the QT interval measures the length of a single heart beat, so they are seeing that in some patients who take azithromycin are developing these uneven heart beats, also known as arrhythmias. And I had heard this from my dad who works with a lot of these drugs/the news, but after more research, I found that these studies only claim that azithromycin has about a 0.8% increase in arrhythmias compared to other antibiotics, and that it was really only seen in patients with pre-existing heart conditions.

Anyway, what I was interested in was how it functions to combat bacterial infections. And it turns out, its super cool! So as you may know from your vast knowledge of biology, ribosomes have two main subunits, a larger one that sits on top of the mRNA, and a lower one that essentially caps the bottom of the mRNA to the rest of the ribosome. In bacteria, the larger subunit is called the “50S” subunit and the smaller one is called the “30S” subunit. So as we know, ribosomes zip across the mRNA, synthesizing a growing peptide chain out from this top, larger subunit. So what I found is that azithromycin actually squeezes itself into the center of this 50S subunit in bacteria, and blocks the addition of any amino acids to the growing peptide chain, arresting any protein synthesis in bacteria. And without being able to produce any proteins, the bacteria die! Below is a PyMol figure I made showing the 50S subunit, with azithromycin in dark blue in the core of the protein. Actually, inhibiting protein synthesis by basically ‘plugging’ the 50S subunit of bacterial ribosomes is what all macrolide antibiotics do, being just one subsection of many types of antibiotics.

Also, during my paper, I started to think about just how crucial it is for azithromycin and these macrolide drugs to interact selectively with bacterial ribosomes, since if they ever interacted with ours too, we would be not so happy (also dead). However, human ribosomes are much larger than bacterial ribosomes (we have 60S and 40S subunits) and are shaped somewhat differently. I believe this may either cause our ribosomes to have differently shaped binding sites and that azithromycin may not have a compatible shape to insert itself there. Also, its possible that the polarity may be slightly different in human vs. bacterial ribosomal binding sites, which would make azithromycin have more favorable interactions with bacterial ribosomes (as you can see, it has many hydrogen bonding possibilities, as well as defined hydrophobic sections). Below I show both the macrolide structure of azithromycin, and where it inserts itself into the 50S subunit. Pretty cool, right!