Bacterial resistance to rifampicin by its modifications

0567965 - MBÚ 2023 RIV CZ eng A - Abstrakt
Balgová, Tamara - Sudzinová, Petra - Šanderová, Hana - Rejman, Dominik - Krásný, Libor
Bacterial resistance to rifampicin by its modifications.
Czech Chemical Society Symposium Series. Roč. 20, č. 6 (2022), s. 380-380. ISSN 2336-7202.
[Annual meeting of the National Institute of Virology and Bacteriology (NIVB) /1./. 30.11.2022-02.12.2022, Kutná Hora]
Grant CEP: GA MŠMT(CZ) LX22NPO5103
Institucionální podpora: RVO:61388971 ; RVO:61388963
Klíčová slova: Rifamycins * RNA polymerase * ADP-ribosyltransferase * glycosyltransferase
Obor OECD: Microbiology
http://www.ccsss.cz/index.php/ccsss/issue/view/37/67

Rifamycins are antibacterial compounds that target RNA polymerase (RNAP). 3D structures of these compounds resemble “baskets” composed of an aliphatic chain (reminding a handle) attached to a naphthalene aromatic core (bottom part of the basket). Rifampicin (syn. rifampin), a semisynthetic compound, is the most clinically relevant rifamycin, used against Gram-positive bacteria, perhaps most notably against mycobacteria that contain serious pathogens such as Mycobacterium tuberculosis. Resistance to rifampicin arises due to mutations in the binding site in RNAP and to various other mechanisms. An important class of rifampicin resistance mechanisms is mediated by four types of modifications of the compound. First, rifampicin can be phosphorylated. This is mediated by a homolog of a phosphoenolpyruvate synthase named rifampicin phosphotransferase (RPH). RPH phosphorylates the hydroxyl group on C21 of the aliphatic chain of rifampicin, disturbing its interaction with the b subunit of RNAP. Second, rifampicin can be ADP-ribosylated. This is mediated by the enzyme ADP-ribosyltransferase (Arr). Rifampicin binds to Arr through main chain atoms of the protein, not utilizing the side chains of the amino acids. For Mycobacterium smegmatis, it was shown that Arr2 binds NAD+ and transfers its ADP-ribose to C23 of rifampicin, replacing the hydroxyl group. This hydroxyl group is important for binding of rifampicin to RNAP and its modification abolishes one of the contacts of rifampicin to the b subunit of the enzyme, providing resistance. Third, rifampicin can be glycosylated. Glycosylation is performed by the enzyme glycosyltransferase (Rgt), the sugar moiety is transplanted onto rifampicin from UDP-glucose. The modification occurs on C23, as in the previous case. Fourth, the closed “basket” structure of rifampicin can be linearized by rifampicin monooxygenase (Rox). Rox transfers a hydroxyl group to C2 of the aromatic core of rifampicin. C-N bond cleavage at C2 ensues, breaking the aliphatic chain. Of these mechanisms, rifampicin glycosylation is perhaps the most abundant mechanism of rifampicin inactivation, at least among soil microorganisms.
Modifications of rifampicin by bacteria inactivate/decrease efficiency of the drug. Conversely, rifampicin is being modified by researchers to overcome bacterial defences against this compound10. It is an arms race and novel modifications are urgently needed, as well as deeper insights into the mechanisms of rifampicin resistance. We will discuss the strategies employed by both bacteria and researchers, describe emerging mechanisms of rifampicin resistance, relevant protein factors involved, such as the RNAP interacting factor HelD (HelR)11,12, and present results about genetic regulatory circuits governing bacterial response to this antibiotic.
Trvalý link: https://hdl.handle.net/11104/0339364