<?xml version="1.0"?>
<ownershipDocument>

    <schemaVersion>X0206</schemaVersion>

    <documentType>3</documentType>

    <periodOfReport>2017-11-01</periodOfReport>

    <noSecuritiesOwned>0</noSecuritiesOwned>

    <issuer>
        <issuerCik>0001701108</issuerCik>
        <issuerName>Spero Therapeutics, Inc.</issuerName>
        <issuerTradingSymbol>SPRO</issuerTradingSymbol>
    </issuer>

    <reportingOwner>
        <reportingOwnerId>
            <rptOwnerCik>0001721017</rptOwnerCik>
            <rptOwnerName>Goyal Vikas</rptOwnerName>
        </reportingOwnerId>
        <reportingOwnerAddress>
            <rptOwnerStreet1>C/O S.R. ONE, LIMITED</rptOwnerStreet1>
            <rptOwnerStreet2>161 WASHINGTON STREET, SUITE 500</rptOwnerStreet2>
            <rptOwnerCity>CONSHOHOCKEN</rptOwnerCity>
            <rptOwnerState>PA</rptOwnerState>
            <rptOwnerZipCode>19428</rptOwnerZipCode>
            <rptOwnerStateDescription></rptOwnerStateDescription>
        </reportingOwnerAddress>
        <reportingOwnerRelationship>
            <isDirector>1</isDirector>
            <isOfficer>0</isOfficer>
            <isTenPercentOwner>0</isTenPercentOwner>
            <isOther>0</isOther>
        </reportingOwnerRelationship>
    </reportingOwner>

    <derivativeTable>
        <derivativeHolding>
            <securityTitle>
                <value>Junior preferred stock</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <footnoteId id="F1"/>
            </conversionOrExercisePrice>
            <exerciseDate>
                <footnoteId id="F1"/>
            </exerciseDate>
            <expirationDate>
                <footnoteId id="F1"/>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>244147</value>
                    <footnoteId id="F5"/>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>I</value>
                </directOrIndirectOwnership>
                <natureOfOwnership>
                    <value>See Footnote</value>
                    <footnoteId id="F6"/>
                </natureOfOwnership>
            </ownershipNature>
        </derivativeHolding>
        <derivativeHolding>
            <securityTitle>
                <value>Series A preferred stock</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <footnoteId id="F2"/>
            </conversionOrExercisePrice>
            <exerciseDate>
                <footnoteId id="F1"/>
            </exerciseDate>
            <expirationDate>
                <footnoteId id="F1"/>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>246272</value>
                    <footnoteId id="F5"/>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>I</value>
                </directOrIndirectOwnership>
                <natureOfOwnership>
                    <value>See Footnote</value>
                    <footnoteId id="F6"/>
                </natureOfOwnership>
            </ownershipNature>
        </derivativeHolding>
        <derivativeHolding>
            <securityTitle>
                <value>Series B preferred stock</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <footnoteId id="F3"/>
            </conversionOrExercisePrice>
            <exerciseDate>
                <footnoteId id="F1"/>
            </exerciseDate>
            <expirationDate>
                <footnoteId id="F1"/>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>328992</value>
                    <footnoteId id="F5"/>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>I</value>
                </directOrIndirectOwnership>
                <natureOfOwnership>
                    <value>See Footnote</value>
                    <footnoteId id="F6"/>
                </natureOfOwnership>
            </ownershipNature>
        </derivativeHolding>
        <derivativeHolding>
            <securityTitle>
                <value>Series C preferred stock</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <footnoteId id="F4"/>
            </conversionOrExercisePrice>
            <exerciseDate>
                <footnoteId id="F1"/>
            </exerciseDate>
            <expirationDate>
                <footnoteId id="F1"/>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>606024</value>
                    <footnoteId id="F5"/>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>I</value>
                </directOrIndirectOwnership>
                <natureOfOwnership>
                    <value>See Footnote</value>
                    <footnoteId id="F6"/>
                </natureOfOwnership>
            </ownershipNature>
        </derivativeHolding>
    </derivativeTable>

    <footnotes>
        <footnote id="F1">The Junior preferred stock is convertible into the respective number of shares of common stock shown in column 3 in each case calculated using the conversion ratio set forth in the Issuer's Amended and Restated Certificate of Incorporation, as amended, at any time at the holder's election and automatically upon the closing of the Issuer's initial public offering.  The shares have no expiration date.</footnote>
        <footnote id="F2">The Series A preferred stock is convertible into the respective number of shares of common stock shown in column 3 in each case calculated using the conversion ratio set forth in the Issuer's Amended and Restated Certificate of Incorporation, as amended, at any time at the holder's election and automatically upon the closing of the Issuer's initial public offering.  The shares have no expiration date.</footnote>
        <footnote id="F3">The Series B preferred stock is convertible into the respective number of shares of common stock shown in column 3 in each case calculated using the conversion ratio set forth in the Issuer's Amended and Restated Certificate of Incorporation, as amended, at any time at the holder's election and automatically upon the closing of the Issuer's initial public offering.  The shares have no expiration date.</footnote>
        <footnote id="F4">The Series C preferred stock is convertible into the respective number of shares of common stock shown in column 3 in each case calculated using the conversion ratio set forth in the Issuer's Amended and Restated Certificate of Incorporation, as amended, at any time at the holder's election and automatically upon the closing of the Issuer's initial public offering.  The shares have no expiration date.</footnote>
        <footnote id="F5">Share numbers give effect to the 1-for-6.0774 reverse stock split of the Issuer's common stock effected on October 20, 2017.</footnote>
        <footnote id="F6">S.R. One, Limited, an indirect, wholly-owned subsidiary of GlaxoSmithKline plc, is the record holder of the shares reported herein.  Vikas Goyal is a Principal at S.R. One, Limited and an employee of GlaxoSmithKline LLC, a wholly-owned subsidiary of GlaxoSmithKline plc.  Mr. Goyal disclaims beneficial ownership of all the shares held by S.R. One, Limited and this report shall not be deemed an admission of beneficial ownership of such shares for the purposes of Section 16 or for any other purpose except to the extent of his pecuniary interest therein.</footnote>
    </footnotes>

    <remarks>Exhibit List

Exhibit 24.1 - Power of Attorney</remarks>

    <ownerSignature>
        <signatureName>/s/ Matthew Tikonoff, Attorney-in-Fact for Vikas Goyal</signatureName>
        <signatureDate>2017-11-01</signatureDate>
    </ownerSignature>
</ownershipDocument>
