Synergists, resistance, management

Considerable interest has developed in resistance management through the use of 1) compounds that are more active against fungicide-resistant biotypes than their sensitive counterparts (i.e., the resistant biotypes exhibit negatively-correlated cross resistance) and 2) compounds that interfere with the resistance mechanism (i.e., synergists). Both approaches to resistance control have been reviewed by De Waard (24,45). 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

In addition, agrochemical companies continue to search for new compounds with novel chemistry and with new modes of action that can be incorporated into crop protection management strategies that will control resistant insects. Furthermore, there is also the opportunity to introduce synergists of insecticides that depress or inhibit the detoxifying enzymes and, thereby, enhance the effectiveness of the compounds. 

RatTa and Priester also referred to two further benefits of the use of synergists. Routine use can he advantageous in (he prevention of selection for resistance, and the use of a synergist which is not as active on a predator as on the pest can he employed in integrated pest manage me nl tlPMy... 

Nonnucleoside RTIs that do not require metabolic activation (e.g., delavirdine and nevirapine, efavirenz, which are not myelosuppressants) and a nucleotide reverse-transcriptase inhibitor (adefovir) have been introduced. Resistance emerges rapidly if these drugs are used as individual agents for management of HIV infection. However, they may provide additive or synergistic activity against HIV if used in combination regimens with NRTIs and/or Pis. 

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