Much of this depends on what other software you will be working with. Any flexible read / write connection with Zotero should probably use the server API ; There are already pretty powerful client libraries in Python and PHP that you can research, and it would be wise to write them in Perl.
If you need only read access or read access in addition to write access, there is a Python library libzotero, which is provided by the wonderful qnotero tool . It opens a read-only connection to the local Zotero database underlying the sqlite database. If you need quick access to reading and searching, this library or its approach will serve you well.
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