Type-II NADH Dehydrogenase (NDH-2): a promising therapeutic target for antitubercular and antibacterial drug discovery

ABSTRACT

Introduction: Tuberculosis (TB) is highly dangerous due to the development of resistance to first-line drugs. Moreover, Mycobacterium tuberculosis (Mtb) has also developed resistance to newly approved antitubercular drug bedaquiline. This necessitates the search for drugs acting on newer molecular targets. The energy metabolism of mycobacteria is the prime focus for the discovery of novel antitubercular drugs. Targeting type-2 NADH dehydrogenase (NDH-2) involved in the production of respiratory ATP could, therefore, be effective in treating the disease.

Areas covered: This review describes the energetics of mycobacteria and the role of NDH-2 in ATP synthesis. Special attention has been given for genetic and chemical validations of NDH-2 as a molecular target. The reported kinetics and crystal structures of NDH-2 have been given in detail for better understanding of the enzyme.

Expert opinion: NDH-2 is an essential enzyme for ATP synthesis and has a potential role in dormancy and persistence of Mtb. The human counterpart lacks this enzyme and hence NDH-2 inhibitors could have more clinical importance. Phenothiazines are potent inhibitor of NDH-2 and are effective against both drug-susceptible and drug-resistant Mtb. Thus, it is highly desirable to optimize phenothiazine class of compounds for the development of next generation anti-TB drugs.

KEYWORDS:

• ATP synthesis
• dormant-TB
• enzyme kinetics
• NDH-2
• resistant-TB
• type-2 NADH dehydrogenase

Article highlights

• In mycobacteria, electrons enter the electron transport chain through the enzyme type-2 NADH dehydrogenase (NDH-2), which has catalytic role in the oxidation of NADH to NAD⁺, followed by reduction of quinone to quinol.

• The NDH-2 enzyme is bound to the periphery of the inner surface of cytoplasmic membrane and may have vital role in providing redox balance.

• Inhibition of NDH-2 will collapse the production of proton motive force, leading to death of Mtb.

• NDH-2 is present in two isoforms (Ndh and NdhA) in Mtb and they were encoded by ndh and ndhA genes respectively.

• Two different catalytic mechanisms have been proposed for the enzyme,

  1. Two-site ping-pong kinetic mechanism, where quinone binds to a site different from the NADH binding site.

  2. Mechanism involving formation of a ternary complex, where a charge transfer complex between the FAD and NAD⁺ was observed and later dissociated by quinone.

• Phenothiazines inhibited both homologues of NDH-2 i.e. Ndh and NdhA, leading to reduction of oxygen intake by mycobacterial membrane vesicles having NADH.

• Quinoline-quinones, quinolinyl-pyrimidines and some antibiotics are also reported to inhibit different bacterial NDH-2.This box summarizes key points contained in the article.

Declaration of interest

S. Sellamuthu is receiving Teaching assistantship from the Ministry of Human Resources and Development, Government of India. M. Singh has received fellowship from the Indian Council of Medical Research, Government of India. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded