Influence of type-2 NADH dehydrogenases on Staphylococcus aureus growth, physiology, and Warburg metabolism

Staphylococcus aureus can grow in anaerobic, microaerobic, and aerobic environments. This versatility requires processes and enzymes for fermentation, and aerobic and anaerobic respiration. Fermentation is the catabolism of organic compounds in which ATP is produced by substrate-level phosphorylation. Respiration is a complex process involving numerous proteins and the transfer of electrons from donors to carriers and acceptors. Central to respiration are NADH dehydrogenases that reduce menaquinone to menaquinol. In S. aureus , reduction of the carrier molecule menaquinone is, in part, accomplished by one of two type-2 NADH dehydrogenases (i.e., NdhC and NdhF). The importance of NdhC and NdhF to S. aureus growth, metabolism, and physiology was assessed using NADH dehydrogenase mutants (i.e., Δ ndhC , Δ ndhF , and Δ ndhF Δ ndhC ) of S. aureus strain Newman. During aerobic cultivation, inactivation of ndhC slightly decreased the growth rate and growth yield relative to the wild-type strain and decreased tricarboxylic acid cycle activity. This was accompanied by a dramatic increase in lactate dehydrogenase-1 accumulation, suggesting that metabolism in ndhC -inactivated strains partially resembled Warburg metabolism. In contrast to NdhC, NdhF was predominantly produced during the post-exponential growth phase, and most effects of ndhF inactivation were moderate. Overall, NdhC and NdhF are differentially produced in S. aureus to regulate metabolism and growth in response to oxygen availability. IMPORTANCE Staphylococcus aureus can grow in many different environments and conditions. This growth versatility is dependent upon its ability to catabolize many different nutrients. These catabolic processes often require the movement of electrons from donors to acceptors in order to complete an enzymatic reaction. A common electron acceptor is the dinucleotide NAD + , which becomes NADH. NADH can then donate electrons to another molecule (i.e., menaquinone); however, electron transfer requires the help of a protein. One such protein is called NADH dehydrogenase. In S. aureus , there are two NADH dehydrogenase proteins (i.e., NdhC and NdhF). We investigated the function of these two proteins in S. aureus growth, a prerequisite for being able to inhibit its growth in or on humans.