{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:46:30Z","timestamp":1789685190963,"version":"4.0.1"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,7,24]]},"abstract":"<jats:p>\n                    Drugs are commonly used in combinations larger than two for treating bacterial infection. However, it is generally impossible to infer directly from the effects of individual drugs the net effect of a multidrug combination. Here we develop a mechanism-independent method for predicting the microbial growth response to combinations of more than two drugs. Performing experiments in both Gram-negative (\n                    <jats:italic>Escherichia coli)<\/jats:italic>\n                    and Gram-positive (\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    ) bacteria, we demonstrate that for a wide range of drugs, the bacterial responses to drug pairs are sufficient to infer the effects of larger drug combinations. To experimentally establish the broad applicability of the method, we use drug combinations comprising protein synthesis inhibitors (macrolides, aminoglycosides, tetracyclines, lincosamides, and chloramphenicol), DNA synthesis inhibitors (fluoroquinolones and quinolones), folic acid synthesis inhibitors (sulfonamides and diaminopyrimidines), cell wall synthesis inhibitors, polypeptide antibiotics, preservatives, and analgesics. Moreover, we show that the microbial responses to these drug combinations can be predicted using a simple formula that should be widely applicable in pharmacology. These findings offer a powerful, readily accessible method for the rational design of candidate therapies using combinations of more than two drugs. In addition, the accurate predictions of this framework raise the question of whether the multidrug response in bacteria obeys statistical, rather than chemical, laws for combinations larger than two.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1201281109","type":"journal-article","created":{"date-parts":[[2012,7,6]],"date-time":"2012-07-06T02:41:28Z","timestamp":1341542488000},"page":"12254-12259","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":142,"title":["Mechanism-independent method for predicting response to multidrug combinations in bacteria"],"prefix":"10.1073","volume":"109","author":[{"given":"Kevin","family":"Wood","sequence":"first","affiliation":[{"name":"FAS Center for Systems Biology, Department of Molecular and Cellular Biology, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Nishida","sequence":"additional","affiliation":[{"name":"FAS Center for Systems Biology, Department of Molecular and Cellular Biology, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo D.","family":"Sontag","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Rutgers University, Piscataway, NJ 08854"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Cluzel","sequence":"additional","affiliation":[{"name":"FAS Center for Systems Biology, Department of Molecular and Cellular Biology, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,7,5]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"e394","article-title":"Infective endocarditis: Diagnosis, antimicrobial therapy, and management of complications: A statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of America","volume":"111","author":"Baddour LM","year":"2005","unstructured":"LM Baddour, et al.; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America, Infective endocarditis: Diagnosis, antimicrobial therapy, and management of complications: A statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of America. 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