As filed with the Securities and Exchange Commission on March 3, 2022

Registration No. 333-         

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

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Form S-8

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REGISTRATION STATEMENT

UNDER

THE SECURITIES ACT OF 1933

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Entasis Therapeutics Holdings Inc.

(Exact name of registrant as specified in its charter)

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 2018 Equity Incentive Plan

2018 Employee Stock Purchase Plan

(Full title of the plans)

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Manoussos Perros, Ph.D.

Chief Executive Officer

Entasis Therapeutics Holdings Inc.

35 Gatehouse Drive

Waltham, MA 02451

(name and address of agent for service)

f(781) 810-0120

(Telephone number, including area code, of agent for service)

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Copies to:

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Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

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If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 7(a)(2)(B) of the Securities Act. ⌧

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EXPLANATORY NOTE

This Registration Statement on Form S-8, or the Registration Statement, is filed by Entasis Therapeutics Holdings Inc., or the Company, for the purpose of registering additional shares of its common stock, par value $0.001 per share, or the Common Stock, under the Company’s 2018 Equity Incentive Plan, or the 2018 Plan and the Company’s 2018 Employee Stock Purchase Plan, or the ESPP.

The number of shares of Common Stock available for issuance under the 2018 Plan is subject to an automatic annual increase on January 1st of each year, for a period of not more than 10 years, commencing on January 1, 2019 and ending on (and including) January 1, 2028, in an amount equal to the lesser of: (a) 4% of the total number of shares of capital stock outstanding on December 31st of the preceding calendar year and (b) a number of shares of Common Stock designated by action of the Company’s board of directors prior to the first day of any calendar year, or the 2018 Plan Provision. Accordingly, the number of shares of Common Stock available for issuance under the 2018 Plan was increased by 1,914,071 shares effective January 1, 2022. This Registration Statement registers the 1,914,071 additional shares of Common Stock available for issuance under the 2018 Plan as a result of the 2018 Plan Provision.

The number of shares of Common Stock available for issuance under the ESPP is subject to an automatic annual increase on January 1st of each year for a period of up to 10 years, commencing on January 1, 2019 and ending on (and including) January 1, 2028. The number of shares added each year will be equal to the lesser of: (a) 1% of the total number of shares of the Company’s capital stock outstanding on December 31 of the preceding calendar year; (b) 250,000 shares of Common Stock and (c) a number of shares of Common Stock designated by action of the Company’s board of directors prior to the first day of any calendar year, or the ESPP Provision. Accordingly, the number of shares of Common Stock available for issuance under the ESPP was increased by 250,000 shares effective January 1, 2022. This Registration Statement registers the 250,000 additional shares of Common Stock available for issuance under the ESPP as a result of the ESPP Provision.

Pursuant to General Instruction E to Form S-8 under the Securities Act, the contents of the Company’s Registration Statements on Form S-8 filed with the Securities and Exchange Commission, or the SEC, on November 14, 2018 (File No. 333-228384), March 29, 2019 (File No. 333-230593), May 7, 2020 (File No. 333-238076), August 6, 2020 (File No. 333-241672) and March 23, 2021 (File No. 333-254607) are incorporated by reference into this Registration Statement.

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PART II

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INFORMATION REQUIRED IN THE REGISTRATION STATEMENT

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Item 3.              Incorporation of Documents by Reference.

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The following documents (File No. 001-38670) previously filed with the SEC are hereby incorporated by reference:

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All documents subsequently filed by the Company pursuant to Section 13(a), 13(c), 14 or 15(d) of the Exchange Act, prior to the filing of a post-effective amendment which indicates that all securities offered hereby have been sold or which deregisters all securities then remaining unsold, shall be deemed to be incorporated by reference into this Registration Statement and to be a part hereof from the date of filing such documents, except as to specific sections of such documents as set forth therein.

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Unless expressly incorporated into this Registration Statement, a report furnished on Form 8-K (or any portion thereof so furnished) prior or subsequent to the date hereof shall not be incorporated by reference into this Registration Statement. Any statement contained in a document incorporated or deemed to be incorporated by reference herein shall

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be deemed to be modified or superseded for purposes of this Registration Statement to the extent that a statement herein or in any subsequently filed document which also is or is deemed to be incorporated by reference herein modifies or supersedes such statement. Any such statement so modified or superseded shall not constitute a part of this Registration Statement, except as so modified or superseded.

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Item 8.                Exhibits.

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*Filed herewith

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SIGNATURES

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Pursuant to the requirements of the Securities Act of 1933, the Registrant certifies that it has reasonable grounds to believe that it meets all of the requirements for filing on Form S-8 and has duly caused this Registration Statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of Waltham, Commonwealth of Massachusetts on March 3, 2022.

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POWER OF ATTORNEY

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KNOW ALL PERSONS BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Manoussos Perros, Ph.D. and Kristie Wagner, and each or any one of them, his or her true and lawful attorney-in-fact and agent, with full power of substitution and resubstitution, for him or her and in his or her name, place and stead, in any and all capacities, to sign any and all amendments (including post-effective amendments) to this Registration Statement, and to file the same, with all exhibits thereto, and other documents in connection therewith, with the Securities and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing requisite and necessary to be done in connection therewith, as fully to all intents and purposes as he or she might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, or any of them, or their or his or her substitutes or substitute, may lawfully do or cause to be done by virtue hereof.

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Pursuant to the requirements of the Securities Act of 1933, as amended, this Registration Statement has been signed by the following persons in the capacities and on the dates indicated.

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Exhibit 5.1

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March 3, 2022

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Entasis Therapeutics Holdings Inc.

35 Gatehouse Drive

Waltham, MA 02451

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Ladies and Gentlemen:

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We have acted as counsel to Entasis Therapeutics Holdings Inc., a Delaware corporation (the “Company”), in connection with the registration by the Company under the Securities Act of 1933, as amended (the “Act”), of 2,164,071 shares of the Company’s common stock, par value $0.001 per share (the “Common Stock”), consisting of 1,914,071 shares of Common Stock (the “Incentive Plan Shares”) issuable under the Company’s 2018 Equity Incentive Plan, as amended (the “Incentive Plan”), and 250,000 shares of Common Stock (the “ESPP Shares,” and together with the Incentive Plan Shares, the “Shares”) issuable under the Company’s 2018 Employee Stock Purchase Plan (the “ESPP”), pursuant to the Registration Statement on Form S-8 filed with the Securities and Exchange Commission on the date hereof (such registration statement is referred to herein as the “Registration Statement”).

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We have reviewed such corporate records, certificates and other documents, and such questions of law, as we have considered necessary or appropriate for the purposes of this opinion. We have assumed that all signatures are genuine, that all documents submitted to us as originals are authentic and that all copies of documents submitted to us conform to the originals.

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We have relied as to certain matters on information obtained from public officials, officers of the Company and other sources believed by us to be responsible.

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Based upon the foregoing, we are of the opinion that the Incentive Plan Shares and the ESPP Shares have been duly authorized and, when issued in accordance with the terms of the Incentive Plan and the ESPP, respectively, and any individual agreements relating to such Shares, the Shares will be validly issued, fully paid and nonassessable.

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We are members of the bar of the District of Columbia. We do not express any opinion herein on any laws other than the General Corporation Law of the State of Delaware and reported judicial decisions interpreting these laws.

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We hereby consent to the filing of this opinion as Exhibit 5.1 to the Registration Statement. In giving such consent, we do not thereby admit that we are in the category of persons whose consent is required under Section 7 of the Act.

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Very truly yours,

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/s/ Covington & Burling LLP

Exhibit 23.1

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Consent of Independent Registered Public Accounting Firm

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We consent to the use of our report dated March 3, 2022, with respect to the consolidated financial statements of Entasis Therapeutics Holdings Inc. incorporated herein by reference.

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EXHIBIT 107

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Calculation of Filing Fee Tables

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Form S-8

(Form Type)

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Entasis Therapeutics Holdings Inc.

(Exact Name of Registrant as Specified in its Charter)

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Table 1: Newly Registered Securities

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