The herbicides that inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPD) are primarily used for weed control in corn, barley, oat, rice, sorghum, sugarcane, and wheat production fields in the United States. The objectives of this review were to summarize 1) the history of HPPD-inhibitor herbicides and their use in the United States; 2) HPPD-inhibitor resistant weeds, their mechanism of resistance, and management; 3) interaction of HPPD-inhibitor herbicides with other herbicides; and 4) the future of HPPD-inhibitor-resistant crops. As of 2022, three broadleaf weeds (Palmer amaranth, waterhemp, and wild radish) have evolved resistance to the HPPD inhibitor. The predominance of metabolic resistance to HPPD inhibitor was found in aforementioned three weed species. Management of HPPD-inhibitor-resistant weeds can be accomplished using alternate herbicides such as glyphosate, glufosinate, 2,4-D, or dicamba; however, metabolic resistance poses a serious challenge, because the weeds may be cross-resistant to other herbicide sites of action, leading to limited herbicide options. An HPPD-inhibitor herbicide is commonly applied with a photosystem II (PS II) inhibitor to increase efficacy and weed control spectrum. The synergism with an HPPD inhibitor arises from depletion of plastoquinones, which allows increased binding of a PS II inhibitor to the D1 protein. New HPPD inhibitors from the azole carboxamides class are in development and expected to be available in the near future. HPPD-inhibitor-resistant crops have been developed through overexpression of a resistant bacterial HPPD enzyme in plants and the overexpression of transgenes for HPPD and a microbial gene that enhances the production of the HPPD substrate. Isoxaflutole-resistant soybean is commercially available, and it is expected that soybean resistant to other HPPD inhibitor herbicides such as mesotrione, stacked with resistance to other herbicides, will be available in the near future.

The benzoylcyclohexane-1,3-diones, the triketones, are potent bleaching herbicides whose structure-activity relationships and physical properties are substantially different from classical bleaching herbicides, which affect phytoene desaturase. The first clue to their unique mechanism of action was the discovery that rats treated with a triketone were found to be tyrosinemic. Additionally, examination of the rat urine revealed the accumulation of p-hydroxyphenylpyruvate (HPP) and p-hydroxyphenyllactate. These results suggested that this chemically induced tyrosinemia was the result of the inhibition of p-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27), and this suggestion was confirmed when a triketone was shown to be a potent inhibitor of rat liver HPPD. In plants, HPPD is a component of the biosynthetic pathway to plastoquinone (PQ), which in turn is a key cofactor of phytoene desaturase. The expectation that triketone-treated plants should accumulate tyrosine while having reduced PQ levels was dramatically demonstrated in the meristematic tissue of ivyleaf morningglory. Plant HPPD, like the mammalian enzyme, was inhibited in vitro by triketones. These biochemical effects provide evidence that the triketone herbicidal mechanism of action is HPPD inhibition leading to a deficiency of PQ, a key cofactor for carotenoid biosynthesis. Other chemical classes of bleaching herbicides were also examined for their ability to elevate tyrosine and deplete PQ as a definitive means of establishing their mode of action and for delineating the structural and physical chemical requirements for an HPPD herbicide. Evidence is provided to support the claim that a 2-benzoylethen-1-ol substructure is the minimum substructure required for a potent HPPD inhibitor.

Field and greenhouse experiments were conducted in Nebraska to (1) confirm the 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting resistant-waterhemp biotype (HPPD-RW) by quantifying the resistance levels in dose-response studies, and (2) to evaluate efficacy of PRE-only, POST-only, and PRE followed by POST herbicide programs for control of HPPD-RW in corn. Greenhouse dose-response studies confirmed that the suspected waterhemp biotype in Nebraska has evolved resistance to HPPD-inhibiting herbicides with a 2- to 18-fold resistance depending upon the type of HPPD-inhibiting herbicide being sprayed. Under field conditions, at 56 d after treatment, ≥90% control of the HPPD-RW was achieved with PRE-applied mesotrione/atrazine/S-metolachlor+acetochlor, pyroxasulfone (180 and 270 g ai ha−1), pyroxasulfone/fluthiacet-methyl/atrazine, and pyroxasulfone+saflufenacil+atrazine. Among POST-only herbicide programs, glyphosate, a premix of mesotrione/atrazine tank-mixed with diflufenzopyr/dicamba, or metribuzin, or glufosinate provided ≥92% HPPD-RW control. Herbicide combinations of different effective sites of action in mixtures provided ≥86% HPPD-RW control in PRE followed by POST herbicide programs. It is concluded that the suspected waterhemp biotype is resistant to HPPD-inhibiting herbicides and alternative herbicide programs are available for effective control in corn. The occurrence of HPPD-RW in Nebraska is significant because it limits the effectiveness of HPPD-inhibiting herbicides.

Field research was conducted in 2010 and 2011 to investigate the efficacy of herbicides for dallisgrass control when applied at various growing (GDD) or cooling degree day (CDD) –based application timings. Herbicide treatments included fluazifop-p-butyl (fluazifop; 105 g ai ha−1), mesotrione (280 g ai ha−1), tembotrione (92 g ai ha−1), topramezone (37 g ai ha−1), and tank mixtures of fluazifop plus mesotrione, tembotrione, or topramezone. Herbicide treatments were applied at either 75, 175, 375, 775 GDD, or 5 CDD. Treated plots were subjected to three tall fescue interseeding regimes: no seeding, seeding in spring, or seeding in fall (0, 353, and 353 kg pure live seed ha−1, respectively). In 2010, dallisgrass control from fluazifop applied at 75, 375, and 775 GDD was poor (< 50%) by 52 wk after treatment (WAT); in 2011, control from fluazifop application at these timings was higher (62 to 72%). When applied at 175 GDD or 5 CDD in 2010 and 2011, dallisgrass control from fluazifop ranged from 79 to 93% at 52 WAT. The addition of mesotrione, tembotrione, or topramezone to fluazifop did not affect dallisgrass control at any application timing, and control provided by these herbicides alone was low (< 65%). Interseeding tall fescue in the fall improved dallisgrass control from herbicides applied at 75 GDD in 2010 and 175, 375, and 775 GDD at 52 WAT in both years. Results suggest that timing of fluazifop applications at 175 GDD and 5 CDD enhances dallisgrass control.

Field studies were conducted in 1999 and 2000 at Simcoe, Ridgetown, and Exeter, Ontario, to evaluate the tolerance of nine sweet corn cultivars to mesotrione, applied preemergence (PRE) at 140 and 280 g ai/ha and postemergence (POST) at 100 and 200 g ai/ha. Urea ammonium nitrate fertilizer (28%) at 2.5% (v/v) and crop oil concentrate at 1% (v/v) were added to POST applications of mesotrione only. All cultivars were tolerant to mesotrione applied PRE. There was no injury, or reductions in plant height or yield with PRE applications of mesotrione at any location in either year. POST applications of mesotrione, particularly at 200 g/ha, caused significant phytotoxicity to ‘Calico Belle’ and ‘Del Monte 2038’. Other cultivars also showed phytotoxic symptoms; however, this injury was much reduced and did not occur at all locations each year. Sweet corn injury by mesotrione increased as rate increased. Del Monte 2038 also had significantly reduced plant height and yields. Other cultivars had no plant height or yield reductions because of POST applications of mesotrione.

Natural herbicides approved in organic agriculture are primarily nonselective burn-down essential oils applied POST. Multiple applications are often required due to their low efficacy. To address this problem, the in vivo herbicidal activity of manuka oil, the essential oil distilled from manuka tree (Leptospermum scoparium J.R. and G. Forst), was tested on selected broadleaf and grass weeds. While manuka oil exhibited good POST activity when applied in combination with a commercial lemongrass oil–based herbicide, it ultimately demonstrated interesting PRE activity, providing control of large crabgrass seedlings at a rate of 3 L ha−1. Manuka oil and its main active ingredient, leptospermone, were stable in soil for up to 7 d and had half-lives of 18 and 15 d, respectively. The systemic activity of manuka oil addresses many of the current limitations associated with natural herbicides. Additionally, its soil persistence opens up a multitude of new possibilities for the use of manuka oil as a tool for weed management and may be a potential bridge between traditional and organic agriculture.