if i am not mistaken, the /etc/network/interfaces file, when using network-manager, should contain only the loopback interface... at least, this is the case on all my computers with network-manager handling all the network devices:
# The loopback network interface
auto lo
iface lo inet loopback
and note the /etc/systemd/system/dbus-org.freedesktop.NetworkManager.service line in the following:
host:# find /etc/ -name *.service
/etc/systemd/system/display-manager.service
/etc/systemd/system/sshd.service
/etc/systemd/system/dbus-org.freedesktop.ModemManager1.service
/etc/systemd/system/dbus-org.freedesktop.Avahi.service
/etc/systemd/system/dbus-org.freedesktop.nm-dispatcher.service
/etc/systemd/system/multi-user.target.wants/pppd-dns.service
/etc/systemd/system/multi-user.target.wants/ssh.service
/etc/systemd/system/multi-user.target.wants/NetworkManager.service
/etc/systemd/system/multi-user.target.wants/dns-clean.service
/etc/systemd/system/multi-user.target.wants/anacron.service
/etc/systemd/system/multi-user.target.wants/cron.service
/etc/systemd/system/multi-user.target.wants/cups-browsed.service
/etc/systemd/system/multi-user.target.wants/vnstat.service
/etc/systemd/system/multi-user.target.wants/smartd.service
/etc/systemd/system/multi-user.target.wants/avahi-daemon.service
/etc/systemd/system/multi-user.target.wants/sidu-base.service
/etc/systemd/system/multi-user.target.wants/ModemManager.service
/etc/systemd/system/multi-user.target.wants/lm-sensors.service
/etc/systemd/system/multi-user.target.wants/pywwetha.service
/etc/systemd/system/printer.target.wants/cups.service
/etc/systemd/system/getty.target.wants/getty@tty1.service
/etc/systemd/system/dbus-org.freedesktop.NetworkManager.service
/etc/systemd/system/sysinit.target.wants/resolvconf.service
/etc/avahi/services/udisks.service