I think I'm having the same issue:

Linux ricardo-N24-25BU 4.8.0-28-generic #30-Ubuntu SMP Fri Nov 11
14:03:52 UTC 2016 x86_64 x86_64 x86_64 GNU/Linux

lsb_release -a
No LSB modules are available.
Distributor ID: Ubuntu
Description:    Ubuntu 16.10
Release:        16.10
Codename:       yakkety

Just upgraded to 16.10 last night, after bootup, I connect to a work VPN
(OpenVPN + Pritunl) which was working ok so far.

route -n shows the new routes, and resolve.conf is correctly updated
with the VPN DNS nameserver

Any direct query: dig, nslookup, ip route get {host} resolves correctly
using the VPN DNS

But any other command: ping, telnet, mysql, etc resolves without the VPN
DNS (unless instructed otherwise explicitely)

Quick solution was:

sudo systemctl restart systemd-resolved.service

You received this bug notification because you are a member of Ubuntu
Touch seeded packages, which is subscribed to systemd in Ubuntu.

  systemd-resolved breaks VPN with split-horizon DNS

Status in systemd:
Status in systemd package in Ubuntu:

Bug description:
  I use a VPN configured with network-manager-openconnect-gnome in which
  a split-horizon DNS setup assigns different addresses to some names
  inside the remote network than the addresses seen for those names from
  outside the remote network.  However, systemd-resolved often decides
  to ignore the VPN’s DNS servers and use the local network’s DNS
  servers to resolve names (whether in the remote domain or not),
  breaking the split-horizon DNS.

  This related bug, reported by Lennart Poettering himself, was closed with the 
current Fedora release at the time reaching EOL:

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