J. Soc. Cosmet. Chem., 29, 733-741 (November 1978) Structure-function relationships of surfactants as antimicrobial agents JON J. KABARA Department of Biomechanics, Michigan State University, East Lansing, M148824. Received April 18, 1978. Presented at Annual Scientific Seminar, Society of Cosmetic Chemists, May 1978, Chicago, Illinois. Synopsis STRUCTURE-FUNCTION RELATIONSHIPS of various classes of SURFACTANTS as ANTIMI- CROBIAL AGENTS have been reviewed. It was concluded that while polar groups of the biocide tend to predict activity against a given genera, the chain length of the lipophilic group determines the most active member of the chemical class. In general, cationic surfactants are more active than anionic and nonionic agents. Optimum chain length for activity is between 10-! 6 carbon atoms. Gram (-) and yeast organisms are affected by the lower chain members while gram (+) organisms are affected by the longer chain surfactants. Nonionics, which in the past were considered not to have antimicrobial activity, were shown to be active when the mono-esters were formed from lauric acid. Because of this new property, nonionics, particularly monolaurin (Lauricidin?M), may be useful germicides in addition to their surface active properties. Their nontoxic and low irritation properties make them ideal candidates for cosmetic and toiletry formulations. INTRODUCTION Surface active agents are defined as substances which alter the energy relationships at interfaces. Compounds displaying surface activity are characterized by containing hy- drophilic (polar) and hydrophobic (hydrocarbon or nonpolar) groups. In our paper the term surfactant was chosen as descriptive of those compounds under discussion. Such terms as wetting agents, detergents or emulsifying agents should be reserved for surfactants denoting specific functions. Before 1930 the lack of success in the search for active antibacterial agents had slowly formed the philosophy that bacteria could never be expected to respond to chemo- therapy. The discovery of antimicrobial sulfonilamides, first observed by Trefouels in Fourneau's laboratory in France in 1935, gave impetus to test other classes of chemicals (1). The recognition and study of the germicidal action of certain surfactants stimulated widespread interest in the possible bactericidal potential of this class of chemicals. For early review of the subject, the reader is referred to Glassman (2). A recent edition of a 1958 treatise is also highly recommended even though the new text is without extensive revision (3). I will limit the scope of my discussion to include only 733

734 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS those germicides which are aliphatic surfactants. My reason for concentrating on ali- phatic rather than aromatic surfactants is their lower toxicity. In general, the lipophilic group of the aliphatic surfactant is metabolized to carbon dioxide and water. Since 1966, our goal has been to discover a highly effective and relatively nontoxic ger- micide. This review is a summary of these efforts. Our findings combined with others have pointed to certain structure-function (antimicrobial) relationships that may have universal application in the germicide field. CHEMICAL STRUCTURE--GENERAL CONSIDERATIONS Compounds exhibiting surface activity are characterized by an appropriate structural balance between one or more water-attracting groups and one or more water-repellent groups. In light of my discussion, the hydrophobic group may be a hydrocarbon chain, branched or straight. Both saturated and unsaturated chains must be considered. The kind, geometric form (cis, trans) and position of unsaturation on antimicrobial properties also must be studied. It is generally recognized that the antimicrobial property of an aliphatic surfactant is dependent on chain length. This relationship is complex since it varies in a nonlinear fashion and is somewhat dependent on the specific class of organism tested. This non- specific drug action is best understood in terms of Ferguson's principle (4). This prin- ciple is modified to include the statement that on ascending a homologous series, although the potency should increase, equipotent concentrations should require increasing thermodynamic concentrations and beyond one particular member the series should become less active. More simply, the antimicrobial affect of an aliphatic surfactant becomes optimal at some specific chain length. This optimum length will vary depending upon the polar group and test organism used. Whether n or isobranched fatty acids are more active is controversial. Recent studies indicate that branched-chain acids, like those of the straight-chain acids, are specific with regard to the test organism. There appears to be little overall difference in bacteri- cidal effect which can be ascribed to branching (5). With a given chain length, the position of the hydrophilic group(s) is an important variable in determining surface properties and biological activity. The kind, geometric isomer and position of unsaturation can influence biological activity. In general, the acetylenic containing fatty acids are more active than the ethylenic members. In the ethylenic series, the cis form is more effective against microorganism than the trans form. The polar or hydrophilic portion of the surfactant determines its class. Among the various classes of surfactants, the cationic and, more particularly, the quaternary am- monium compounds have high commercial application. The cationic compounds are by far the most effective wide-spectrum germicides (6). This series can kill or inhibit growth of organisms over a rather wide pH range. The anionic surfactants are frequently active only against gram (+) and yeast organisms and are rarely effective against gram (-) strains. Their action is less rapid than the cationics and is more sus- ceptible to changes in the pH of the system. The nonionic surfactants are not generally considered to be germicidal. However our own research on this group has indicated otherwise. Suffice to say that esters of polyhydric alcohols, amides and aminimides are nonionic surfactants but still have good germicidal properties, as will be discussed later.