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Monkeypox virus (MPXV) has caused a large pandemic outbreak in 2022 with more than 90.000 confirmed cases and 181 deaths. Notably, signs of microevolution and host adaption have been observed. Here, we demonstrate that viral genomes from Franconia, Bavaria acquired different mutations. Three isolates obtained from diagnostic samples, submitted from suspected Mpox cases, show differences in their replication capacities. One MPXV isolate which shows the fastest replication kinetics and higher viral loads, possesses a unique non-synonymous mutation (D616L) in the A11L protein (gene OPG136), which encodes for a protein that is part of a major viral core structure. In regard to pandemic preparedness and future outbreaks, we analyzed the antiviral activity of dihydroorotate dehydrogenase (DHODH) inhibitors, and show that they are active against MPXV, vaccinia virus (VACV), and cowpox virus (CPXV) and therefore likely against orthopoxviruses in general. In agreement with that, we also demonstrated that chemical optimization leads to compounds with EC 50 values in the sub-nanomolar range, associated with low cytotoxicity, which forms a good basis for future drug development from this chemical series., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.G. and H.K. have a patent application WO2023/118576 filed covering the new DHODH inhibitors., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)