I'm playing on "normal" difficulty, am currently level 13 with Guns at 70. Most enemies take most of my shots unharmed with their Damage Threshold. I'm mostly using the Grunt weapons with the perk. I have Hand Loader but have not looked into the effects of the different kinds of ammunition yet. I suppose they can make a noticeable difference. I mostly use standard ammunition or surplus. My secondary weapon is Chance's knife with Melee at 50.

I'm sometimes using up to approx. 100+ bullets on single enemies. How can I get more damage out of guns?

Maybe focus on using AP rounds. They reduce DT and make enemies weaker.

Hmmm. Generally, by level 5 on normal difficulty on the Vanilla game I can destroy almost anything, it seems. Get your hands on something with a moderate damage output but a really high DPS. The Service Rife or Light Machine Gun for example. Get some AP rounds and you should be able to mow down enemies.

Make sure that your weapons are in good condition and that you meet the Strength requirements. Of course, aim for parts that will do more damage and more crit damage i.e. the head.

Don't forget to pop a psycho every once in a while if you are in a tough spot.

Brahman Steak will increase strength +1 for a while, so if you are going survival I would stock up on those. Get a shotgun for close quarters. The Riot Shotgun matched with the Shotgun Surgeon perk should let you blast through even the toughest baddies. Really focus on the perks that give + damage towards everything (obvious).

The biggest switch you can probably make right now is to stock up on AP.

If you're going up against enemies with high DT, you really need to use the armor piercing and higher-powered ammunition types if you want to actually damage them. Start putting that Hand Loader perk to use. You can buy decent quantities of primers, powders and other reloading supplies from the Gun Runners or the Great Khan armorer (you have to be Accepted with the Khans before she trades with you), or you can break down your standard ammo types at the reloading bench and get the components that way.

In my games, by the time I'm at the point where you're at now, the only reason I stock up on standard type ammo is to use it as raw material for my favorite reloading bench recipes.

Exactly which weapons are you using then? That could be part of your problem right there. If a Service Rifle is your main weapon, start thinking about upgrading to a Marksman Carbine instead. And yes, you should be making better use of the different ammo types. If you see that red shield coming up as you shoot them, then you need to switch to Armour Piercing rounds. That will make a big difference. While standard rounds still do some damage against enemies with a high DT, it's a very small amount. So you'll end up with situation you're describing of needing 100+ rounds to kill them.

Depends which guns

I believe the highest DT level you can encounter is 15 for a Deathclaw or a Super Mutant, 18 for a Giant Radscorpion and 31 for a Brotherhood Paladin with T51 armor and helmet.

Now let's do the ammo math:

First, make sure you don't use HP ammo against high DT enemies. HP ammo multiplies DT by 3

Second, SMGs and pistols are generally weak against high DT opponents, so stick with automatics, rifles and shotguns.

.308 and 5.56 armor piercing ammo reduced DT by 15. Automatic Rifle or LMG with armor-piercing 5.56 will reliably defeat most things. Absent those, Battle Rifle works as well, given enough distance and / or VATS action points.

12 gauge + Shotgun Surgeon = -10DT. With flechettes = 16DT. Riot Shotgun with flechettes or slugs will kill anything; with And Stay Back, one-on-one Deathclaw or Giant Rad fights are easy.

5mm ammo has inherent -10DT. It is plentiful and can be bought cheap, so Assault Carbine can be a pretty good choice. 5mm AP ammo has -25DT, nullifying the DT of anything that's not a Brotherhood Paladin in power armor.