Rifabutin Suppresses Inducible Clarithromycin Resistance in <i>Mycobacterium abscessus</i> by Blocking Induction of <i>whiB7</i> and <i>erm41</i>

• Main Authors: Dinah Binte Aziz (Author), Mei Lin Go (Author), Thomas Dick (Author)
• Format: Book
• Published: MDPI AG, 2020-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by <i>Mycobacterium abscessus (Mab)</i>. However, many strains harbor the CLR-inducible CLR resistance gene <i>erm41,</i> encoding a ribosome methylase. Induction of <i>erm41</i> is mediated by the transcription factor <i>whiB7</i>. We hypothesized that an inhibitor of RNA synthesis should be able to block the <i>whiB7&#8722;erm41</i> induction response to CLR exposure and thus suppress CLR resistance. Recently, we discovered that the rifampicin analog rifabutin (RFB) shows attractive potency against <i>Mab</i>. To determine whether RFB-CLR combinations are synergistic, a checkerboard analysis against a collection of <i>erm41</i> positive and negative <i>Mab</i> strains was carried out. This revealed synergy of the two drugs for <i>erm41</i> positive but not for <i>erm41</i> negative strains. To determine whether RFB&#8217;s potentiation effect was due to inhibition of the transcriptional induction of the <i>whiB</i>7&#8722;<i>erm41</i> resistance system, we measured the effect of CLR alone and in combination with RFB on <i>whiB7</i> and <i>erm41</i> mRNA levels. CLR alone strongly induced <i>whiB7</i> and <i>erm41</i> expression as expected. The synergistic, growth-inhibiting combination of RFB with CLR blocked induction of both genes. These results suggest that RFB suppresses inducible CLR resistance by preventing induction of <i>whiB</i>7 and <i>erm41</i> expression.

Item Description

2079-6382
10.3390/antibiotics9020072