Drug Resistance in MRSA is Finely-tuned

Scanning electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, yellow) surrounded by cellular debris. Credit: NIAID

In hindsight, shoving my hand into a narrow drinking glass wasn’t such a good idea.  I learned this the hard way a few years ago while vigorously scrubbing the inside of a glass with a sponge. When the glass shattered in my hands, one of the shards cut the base of my index finger–right by the the knuckle–and required a trip to the local urgent care center. After being stitched up, I was sent home with some antibiotic ointment, extra gauze, and instructions to keep the wound clean. And that’s when things got worse.

Several days later, my finger became red, inflamed, and tender to the touch. There was also stomach-turning pus oozing out of the wound. Fearing that it was infected, I went back to the the urgent care center where the doctor took one look at my wound and then stated the obvious, “That looks infected.” A swab sample was taken from my wound to start a bacterial culture, which would be used to identify the nature of the infection. Since it would take a few days for the results to come back from the lab, she preemptively started me on a course of antibiotics. At the end of the week, there was a message left on my voicemail. The culture was positive for methicillin-resistant Staphylococcus aureus (MRSA).

MRSA-infected finger

This was cause for concern because MRSA is a bacterial pathogen that, once it enters the bloodstream, can cause severe to life-threatening infections. MRSA is also notoriously difficult to treat because it is resistant to β-lactams, a class of antibiotics generally prescribed as the first line of defense against normal staph infections. β-lactams, which include drugs like penicillin, oxacillin, and methicillin, kill bacteria by preventing the synthesis of bacterial cell walls–without which bacteria cannot survive. These drugs accomplish this by glomming onto and inactivating penicillin-binding protein (PBP), an enzyme that makes an essential component of bacterial cell walls. MRSA strains, however, are resistant to β-lactam drugs because they carry a gene called mecA. The mecA gene encodes a different form of penicillin-binding protein, PBP2a, which β-lactam drugs cannot inactivate, thus allowing normal cell wall synthesis to occur even in the presence of these drugs.

Methicillin-resistant Staphylococcus aureus (MRSA) Bacteria

Scanning electron micrograph of methicillin-resistant Staphylococcus aureus bacteria (yellow, round items) killing and escaping from a human white cell. Credit: NIAID

MRSA infections have long been associated with health care settings such as hospitals and nursing homes. These settings, characterized by a sick general population coupled with high antibiotic usage which selects for drug-resistance, are a perfect environment for MRSA strains to gain a foothold. Given that I had my stitches done at an urgent care center I just assumed that’s where I came into contact with MRSA.

In recent years, however, community-acquired MRSA (CA-MRSA) infections have been on the rise. These are infections contracted from settings like schools, childcare centers, gyms, and prisons. Infections caused by CA-MRSA strains are a particular concern because they are more virulent, spread more rapidly, and can cause more severe infections than its healthcare-acquired MRSA (HA-MRSA) counterparts. What’s worse is the line between the two are blurring as HA-MRSA strains move out into the community and CA-MRSA moves into the hospitals. Because of the increased virulence of CA-MRSA strains there are fears that these strains will eventually replace HA-MRSA strains in healthcare settings–although a recent model published in PLOS Pathogens suggests otherwise[1].

How MRSA developed β-lactam resistance is still unclear. While there are quite a few different strains of MRSA (some of which have also developed resistance to other classes of drugs) they all carry the mecA gene. The mecA gene, in turn, is part of a larger piece of foreign DNA known as the SCCmec element, which is not normally found in S. aureus. Since bacteria are quite adept at exchanging DNA with each other, scientists speculate that the SCCmec element found its way into a normal staph strain from an as-of-yet identified trading partner. This process of swapping and transferring DNA is known as horizontal gene transfer.

Interestingly, MRSA has a finely-tuned, “on-demand system” that turns mecA expression on in the presence of β-lactam drugs, while keeping expression turned off in the absence of these drugs. This regulation is carried out by proteins whose genes are also found on the SCCmec element. In the absence of β-lactams–when the bacteria doesn’t need the drug-resistant PBP2a protein around– the expression of mecA is kept in check by the protein MecI. MecI binds to the DNA promoter region of mecAand prevents gene transcription. However, in the presence of β-lactam drugs the bacteria needs PBP2a around in order to survive. In this case, expression of mecA is turned on through the action of the cell surface protein MecR1 whose job is to keep an eye out for β-lactams. When MecR1 detects the presence of β-lactams, it instructs the bacterial cell to break down the MecI inhibitor. This allows expression of the mecA gene that is essential for the bacteria’s survival to occur.

Figure 10. Model for the mecA induction by MecR1-MecI-MecR2.In the presence of a β-lactam antibiotic, MecR1 is activated and rapidly induces the expression of mecA and mecR1-mecI-mecR2. The anti-repressor activity of MecR2 is essential to sustain the mecA induction since it promotes the inactivation of MecI by proteolytic cleavage. In the absence of β-lactams, MecR1 is not activated and a steady state is established with stable MecI-dimers bound to the mecA promoter and residual copies of MecR1 at the cell membrane [2].

Recently, researchers from Portugal have identified and characterized another gene on the SCC element called mecR2 [2]. As it turns out the MecR2 protein is another component of the finely-tuned, “on-demand system”that regulates mecA expression.  When MRSA bacteria encounter β-lactam drugs it starts ramping up the production of MecR2 protein. MecR2, in turn, knocks the MecI inhibitor protein off of the mecA gene promoter, thereby increasing mecA expression. The researchers speculate that the dislodged MecI protein becomes unstable and is then degraded inside the bacterial cell.

Importantly, the researchers demonstrated that in order to get the optimal expression of mecA that would confer resistance to β-lactam drugs, the bacteria needed MecR2 protein around. When they removed the mecR2 gene, the bacteria once again became sensitive to the β-lactam drug oxacillin, which coincided with a decrease in mecA expression. This research not only helps further our understanding of drug resistance in MRSA but also highlights new targets for therapeutics. For instance, drugs could be designed that either short circuit the ability of MecR1 to alert the bacterial cell to the presence of β-lactam drugs or prevent MecR2 from dislodging the MecI inhibitor from the mecA promoter, thereby keeping mecAexpression in check.

As for my finger and me, we made it out of the MRSA scare relatively unscathed–other than a barely noticeable scar at the base of my index finger. Once the lab results came back positive for MRSA, the doctor switched my prescription to Bactrim. Luckily for me, I wasn’t dealing with one of the multi-drug resistant varieties of the bug so the infection cleared in a few days.

References:

1. Kouyos R, Klein E, Grenfell B (2013) Hospital-Community Interactions Foster Coexistence between Methicillin-Resistant Strains of Staphylococcus aureus. PLoS Pathog 9(2): e1003134. doi:10.1371/journal.ppat.1003134

2. Arêde P, Milheiriço C, de Lencastre H, Oliveira DC (2012) The Anti-Repressor MecR2 Promotes the Proteolysis of the mecA Repressor and Enables Optimal Expression of β-lactam Resistance in MRSA. PLoS Pathog 8(7): e1002816. doi:10.1371/journal.ppat.1002816

 

Creative Commons License
Drug Resistance in MRSA is Finely-tuned by Public Health, unless otherwise expressly stated, is licensed under a Creative Commons Attribution 3.0 Unported License.

This entry was posted in Uncategorized and tagged , , , , , . Bookmark the permalink.

One Response to Drug Resistance in MRSA is Finely-tuned

  1. Pingback: Drug Resistance in MRSA is Finely-tuned | Amasian Science

Add Comment Register



Leave a Reply

Your email address will not be published. Required fields are marked *

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>