Spero Therapeutics, Inc.

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

SCHEDULE 14A

Proxy Statement Pursuant to Section 14(a) of the

Securities Exchange Act of 1934

(Amendment No. )

Filed by the Registrant ☒

Filed by a Party other than the Registrant ☐

Check the appropriate box:

Spero Therapeutics, Inc.

(Name of Registrant as Specified in its Charter)

(Name of Person(s) Filing Proxy Statement, if other than the Registrant)

Payment of Filing Fee (Check all boxes that apply):

April 27, 2026

To Our Stockholders:

You are cordially invited to attend the 2026 annual meeting of stockholders of Spero Therapeutics, Inc.to be held at 9:00 a.m. Eastern Time on Tuesday, June 23, 2026. This year’s annual meeting will be conducted virtually via live audio webcast. You will be able to attend the annual meeting, vote and submit your questions during the annual meeting by visiting www.virtualshareholdermeeting.com/SPRO2026. You will not be able to attend the annual meeting in person.

More information regarding the meeting, the business to be conducted at the meeting, and information about Spero Therapeutics, Inc. that you should consider prior to voting your shares are described in the enclosed proxy statement.

At the annual meeting, we will ask stockholders to (i) elect two persons to our Board of Directors; (ii) ratify the appointment of PricewaterhouseCoopers LLP as our independent registered public accounting firm for our fiscal year ending December 31, 2026; (iii) approve by an advisory vote the compensation of our named executive officers, as disclosed in this proxy statement; (iv) approve an amendment to our Amended and Restated Certificate of Incorporation to increase the total number of shares of common stock authorized for issuance thereunder from 120,000,000 shares to 240,000,000 shares; and (v) approve the Spero Therapeutics, Inc. 2026 Stock Incentive Plan. Our Board of Directors recommends the approval of each of these proposals. Any other business that may properly come before the meeting will be transacted as such.

We have elected to provide access to our proxy materials over the internet under the U.S. Securities and Exchange Commission’s “notice and access” rules. This delivery process allows us to provide stockholders with the information they need, while at the same time conserving natural resources and lowering the cost of delivery. Accordingly, on or about April 27, 2026, we intend to begin sending to our stockholders a Notice of Internet Availability of Proxy Materials (the “Notice”) containing instructions on how to access our proxy statement for our 2026 annual meeting of stockholders and our 2025 annual report to stockholders, which includes our Annual Report on Form 10-K for the fiscal year ended December 31, 2025. The Notice also provides instructions on how to vote online or by telephone, how to access the virtual annual meeting and how to receive a paper copy of the proxy materials by mail.

Your vote is important, and we hope that all stockholders will be able to participate in the annual meeting. Whether you plan to attend the annual meeting or not, it is important that you cast your vote either virtually at the annual meeting or by proxy so that your shares will be represented and voted at the meeting. We encourage you to read this proxy statement and submit your proxy or voting instructions as soon as possible by following the instructions in the Notice and submitting your proxy by the internet, telephone, or by signing, dating and returning your proxy card.

Thank you for your continued interest in and support of Spero Therapeutics, Inc.

Sincerely,

President, Chief Executive Officer and Chief Financial Officer

April 27, 2026

NOTICE OF 2026 ANNUAL MEETING OF STOCKHOLDERS

TIME: 9:00 a.m. Eastern Time

DATE: Tuesday, June 23, 2026

ACCESS: www.virtualshareholdermeeting.com/SPRO2026

This year’s annual meeting of stockholders will be a virtual meeting via live audio webcast on the Internet. You will be able to attend the annual meeting, vote and submit your questions during the meeting by visiting www.virtualshareholdermeeting.com/SPRO2026 and entering the 16-digit control number included in the Notice of Internet Availability of Proxy Materials or proxy card that you receive. For further information about the virtual annual meeting, please see the Questions and Answers about the Annual Meeting beginning on page 4.

PURPOSES:

WHO MAY VOTE:

You may vote if you were the record owner of Spero Therapeutics, Inc. common stock at the close of business on April 24, 2026.

Upon request, a list of stockholders of record will be available for examination by any stockholder for any purpose germane to the meeting for a period of 10 days ending on the day before the annual meeting date at our principal executive offices located at 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139.

All stockholders are cordially invited to attend the annual meeting. Whether you plan to attend the annual meeting or not, we urge you to vote and submit your proxy by the Internet, telephone or mail by following the instructions in the Notice of Internet Availability of Proxy Materials that you previously received and as described in this proxy statement in order to ensure the presence of a quorum. You may change or revoke your proxy at any time before it is voted at the meeting.

BY ORDER OF THE BOARD OF DIRECTORS

President, Chief Executive Officer and Chief Financial Officer