<?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>0001720988</rptOwnerCik>
            <rptOwnerName>Halse Reza</rptOwnerName>
        </reportingOwnerId>
        <reportingOwnerAddress>
            <rptOwnerStreet1>C/O MERCK RESEARCH LABORATORIES</rptOwnerStreet1>
            <rptOwnerStreet2>320 BENT ST.</rptOwnerStreet2>
            <rptOwnerCity>CAMBRIDGE</rptOwnerCity>
            <rptOwnerState>MA</rptOwnerState>
            <rptOwnerZipCode>02141</rptOwnerZipCode>
            <rptOwnerStateDescription></rptOwnerStateDescription>
        </reportingOwnerAddress>
        <reportingOwnerRelationship>
            <isDirector>1</isDirector>
            <isOfficer>0</isOfficer>
            <isTenPercentOwner>0</isTenPercentOwner>
            <isOther>0</isOther>
        </reportingOwnerRelationship>
    </reportingOwner>

    <derivativeTable>
        <derivativeHolding>
            <securityTitle>
                <value>Series A 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>96367</value>
                    <footnoteId id="F2"/>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>I</value>
                </directOrIndirectOwnership>
                <natureOfOwnership>
                    <value>MRL Ventures Fund, LLC</value>
                    <footnoteId id="F3"/>
                </natureOfOwnership>
            </ownershipNature>
        </derivativeHolding>
        <derivativeHolding>
            <securityTitle>
                <value>Series B Preferred Stock</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <footnoteId id="F4"/>
            </conversionOrExercisePrice>
            <exerciseDate>
                <footnoteId id="F4"/>
            </exerciseDate>
            <expirationDate>
                <footnoteId id="F4"/>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>328992</value>
                    <footnoteId id="F2"/>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>I</value>
                </directOrIndirectOwnership>
                <natureOfOwnership>
                    <value>MRL Ventures Fund, LLC</value>
                    <footnoteId id="F3"/>
                </natureOfOwnership>
            </ownershipNature>
        </derivativeHolding>
        <derivativeHolding>
            <securityTitle>
                <value>Series C Preferred Stock</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <footnoteId id="F5"/>
            </conversionOrExercisePrice>
            <exerciseDate>
                <footnoteId id="F5"/>
            </exerciseDate>
            <expirationDate>
                <footnoteId id="F5"/>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>317726</value>
                    <footnoteId id="F2"/>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>I</value>
                </directOrIndirectOwnership>
                <natureOfOwnership>
                    <value>MRL Ventures Fund, LLC</value>
                    <footnoteId id="F3"/>
                </natureOfOwnership>
            </ownershipNature>
        </derivativeHolding>
    </derivativeTable>

    <footnotes>
        <footnote id="F1">The shares of Series A preferred stock are convertible into the number of shares of common stock shown in Column 3, 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">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="F3">Shares held by MRL Ventures Fund, LLC. The Reporting Person is the President of MRL Ventures Fund, LLC.  The Reporting Person shares voting and investment power with respect to the shares held by MRL Ventures Fund, LLC and disclaims beneficial ownership of such shares except to the extent of his pecuniary interest therein.</footnote>
        <footnote id="F4">The shares of Series B preferred stock are convertible into the number of shares of common stock shown in Column 3, 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">The shares of Series C preferred stock are convertible into the number of shares of common stock shown in Column 3, 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>
    </footnotes>

    <remarks>Exhibit 24.1 - Power of Attorney</remarks>

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