(CNN) -- President Obama hosts leaders from 46 countries for a two-day nuclear security summit starting Monday that will focus on how to better safeguard weapons materials, both old and new, to keep them out of the hands of terrorists.

The gathering at the Walter E. Washington Convention Center in the nation's capital is considered an unprecedented effort to rally global action on securing vulnerable nuclear materials.

It also is the centerpiece of a major Obama objective aimed at preventing the spread of nuclear weapons and technology.

As the summit begins, the United States is negotiating with the four other permanent members of the United Nations Security Council on tougher sanctions against Iran over its nuclear ambitions.

"The central focus of this nuclear summit is the fact that the single biggest threat to U.S. security, both short term, medium term and long term, would be the possibility of a terrorist organization obtaining a nuclear weapon," Obama said Sunday, appearing with South African President Jacob Zuma in Washington.

"This is something that could change the security landscape in this country and around the world for years to come," Obama said. "If there was ever a detonation in New York City, or London, or Johannesburg, the ramifications -- economically, politically and from a security perspective -- would be devastating. We know that organizations like al Qaeda are in the process of trying to secure nuclear weapons or other weapons of mass destruction and would have no compunction at using them."

Obama signed a new treaty with Russia last week to reduce the nuclear stockpiles of both nations, and his administration issued a revised U.S. nuclear arms strategy intended to reinforce the nation's nuclear deterrent while isolating terrorists and rogue states that fail to comply with international regulations.

It all fits together as an ambitious effort to mobilize a unified global effort against nuclear proliferation, Secretary of State Hillary Clinton and Defense Secretary Robert Gates said in interviews broadcast Sunday.