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    Mechanisms of Action of Disinfectants

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    Biology, Chemistry

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    INTERNATIONAL BIODETERIORATION & ELSEVIER International Biodeterioration & Biodegradation 41 (1998) 261-268 ae Mechanisms of action of disinfectants S. P. Denyer** G. S. A. B. Stewart? Department of Pharmacy. University of Brighton. Leves Road, Brighton, BN2 4G, UK “Department of Pharmaceutical Sciences, Unierity of Notngham. University Park, Nottingham, NGF 2RD, UK Accepted: 29 Jansary 1998 Abstract Disinfectants and biocides are a chemically diverse group of agents which are generally considered to exhibit poor selective toxicity This should not be mistaken for poor target specificity, however, and much is now known concerning the damaging interactions ‘which may arise between bacterial cell and disinfectant agent. Critical governing features of these interactions are the physicochemical characteristics of the chemical agent, cell morphology, and the physiological status of the microorganism, Antibacterial events include membrane disruption, macromolecule dysfunction, and metabolic inhibition; the consequential effect is determined by the relative contributions) of the target(s) to microbial cell survival and the possible initiation of self-destructive processes, Disinfection kinetics offer a measure to differentiate between physiochemical and chemical interactions. Increasingly demanding disinfectant applications require more sophisticated use of biocidal systems. Approaches include: agents in combination, whereby a knowledge of mechanism of action assists in designing optimal mixtures; intracellular biocide delivery, using cellular transport processes to overcome cellular barriers; and targeted donation of biocide from delivery systems, requiring an understanding of target reactivity. ‘A knowledge of disinfection mechanisms provides a basis from which novel chemistries and synergistic combinations may be developed. © 1998 Elsevier Science Ld, All rights reserved, ‘Keywords: Disinfectants; Mode of action; Cellular targets; Antibacterial stv 1. Introduction Disinfectants, or chemical biocides to use a more general term, differ from antibiotic agents in their relative lack of selective toxicity and an often implied lack of target specificity. The former characteristic leads to an ever- increasing pressure to reduce concentrations used and maximise efficacy, while the latter assumption dissuades ‘against rational design and encourages empirical solu- tions to the former problem. A careful examination of the literature however, discloses that the basis of biocide action offers a fertile area for scientific exploration with the potential to establish principles by which improved agents can be developed, Thus, mechanism of action studies can provide direction to novel chemistries and delivery systems, offer predictive capability for com- bination biocides, may give clues to the basis of unwanted toxicity, and can help elaborate the often complex homeostatic processes associated with cell survival. This review seeks to summarise the principal anti- bacterial lesions associated with chemical biocides and “oresponding author. '$0964-8305/98/S19.00 ©) 1998 Elsevce Science Lt. Al rights reserved. Pll: $0964~8308198}00023-7 to present a view on possible future developments; the methods employed to establish these lesions are discussed in an earlier treatment by Denyer and Hugo (1991a). More detailed examination of individual agents can be found in the reviews and monographs of Hugo (1991, 1992, 1995); Hugo and Russell (1992); Paulus (1991, 1993). A broader perspective has recently been published by Russell etal. (1997) 2. Early stages of cell-biocide interaction ‘The vegetative bacterial cell offers three broad regions for biocide interaction: the eell wall, cytoplasmic mem- brane and cytoplasm (Fig. 1). Biocide access to these regions is determined by extracellular material, cell mor- phology and cellular chemical composition; phenotypic ‘variation in cell physiology may lead to intrinsic resist- ance (Nicas and Hancock, 1980; Broxton et al., 1984; Wright and Gilbert, 1987; Brown et al., 1990). The initial interaction with the bacterial cell is described by the uptake isotherm (Denyer, 1990); effec- tive biocide action requires subsequent partitioning of the sorbed biocide to the target site followed by accumu- S.P. Denyer and G.S.A.B, StewartInternational Biodeerioration & Biodegradation 1 (1998) 261-268 Gram negative | Gram positive Cell wall Peptidogivcan | & LPS) | “Assembly & structure Porins { Les = (outer membrane) iyloplasmic membrane * Structural integrity # Respiratory chain and membrane-bound enzymes « Transport mechanisms « Energy coupling processes Cell wall peptidoglycan Cytoplasmic membrane Cytoplasm » Anabolic reactions * Catabolic reactions «Nucleic acids Fig. 1, Potential targets for biocides (eproduced with permission from Denver, 1995), lation to damaging levels, characteristics strongly influ- enced by biocide physicochemistry (Denyer, 1995). In progression to their targets, biocides encounter a variety Of structures; experience shows that the lipidie outer ‘membrane of the Gram-negative bacterium is dominant among these. Hydrophilic biocides of molecular weight Tess than 600 Da are very likely to pass through the wate filled porins; for other agents of greater size or lipo- philicity this structure is likely to offer a quite con- siderable hindrance to passage (Russell, 1991; Gilbert and Wright, 1987). Frequently, penetration must then be assisted by localised destabilising effects in the outer membrane arising from damaging interactions (eg EDTA; Russell, 1991), by biocide molecular co-associ- ation altering the physicochemistry of partition Gilbert and Al-Taae, 1985; Kanazawa et al., 1995) or through formulation design. Initial sorption and progression to, and accumulation at, target are rarely instantaneous events and can therefore be influenced by factors such as biocide concentration, temperature and formulation; pH will affect both the charge on microbial structures and the ionization of ionizable biocides, again affecting the initial interactive stages (Richards et al., 1995). Thus extraneous factors may profoundly influence the rate and. extent of cell injury without necessarily invoking any direct effect on the mechanism of action, 3. Potential targets for biocides From the perspective of functionality the cell wall, comprising an open network of peptidoglycan (with a lipopolysaccharide overlayer for Gram-negative bacteria), provides for little more than structural integ- rity; in this regard, it serves as an excellent target for antibiotics but rarely proves a suitable site for direct biocide action. The cytoplasmic membrane however offersa rich matrix of balanced interactions between pho- spholipid and enzymic/structural protein, ensuring a con- trolled impermeability and topological organisation by which intracellular homeostasis and vectorial trans- portimetabolism are maintained (Singer and Nicolson, 1972; Salton and Owen, 1976; Kroll and Patchett, 1991); this multiplicity of critically sensitive functions and the large expanse for interaction predispose this region to biocide attack. Many catabolic and anabolic processes are vested in the cytoplasm, together with the necessary replicative machinery; this region also affords a diverse range of target processes but, by virtue of its inclusion within the cytoplasmic membrane, it is the last region for biocide accumulation. Thus, the target most frequently cited in the biocide literature is the cytoplasmic membrane, particularly in investigations of bacteriostasis where biocide concentrations are relatively low and the membrane appears especially sensitive to functional per- turbation (Fig. 1). At disinfection levels however, it may bbe more difficult to distinguish between lesions occurring at the membrane and the cytoplasm. Biocide physicochemistry will affect the efficacy of tar- get interaction. For electrophilic agents, which include the aldehydes, active-halogen compounds, isothiazo- Tinones and the N-haloalkylthio biocides, reactivity is dependant upon low steric hindrance and strongeelectron- SP. Denyer and G.S.A.B. Stewart/Interntiona Biodeerioration & Biodegradation $1 (1998) 261-268 withdrawing capability, Membrane perturbing agents are governed in their interactions by the balance between hydrophobic and polar groups; quantitative structure activity relationships equate partition coefficients with the activity of phenols, weak acids and their esters, while the positively charged head group and alkyl chain length determine the relative efficiencies of cationic surface- active agents. A close examination of biocide-target inter- actions indicates a differentiation between strong chemi- cal (covalent) or ionic interactions and those associated with physical partitioning. The former interactions are characterised by a general tolerance to concentration change often requiring the use of specific neutralizers for inactivation, while those driven by partitioning are readily inactivated by dilution. This behaviour is reflected in the concentration exponent (Table 1): knowledge of this parameter and its determination in disinfection kin- ties (Reichart, 1994) may allow presumptive conclusions to be drawn regarding the mechanisms of inter- action/action (Hugo and Denyer, 1987). 4, Mechanisms of antibacterial action The classical approach to determining a mechanism of action relies upon establishing a correlation between, concentrations initiating bacteriostatic or bactericidal effects and those precipitating specific biochemical or physiological changes (Bloomfield, 1991); where cor- relation is seen a causal relationship is implied. As might be expected, experimental conditions may profoundly affect the concentration threshold of whole cell events and considerable care must be taken to properly account, for experimental artefacts (Russell et al., 1973; Denyer and Hugo, 1991a). An alternative approach may be to explore the relationship of severity of effect at the cellular and biochemical levels with some intrinsic property of the biocide; concentration exponent, sorption profiles, rate kinetics and temperature coefficients have all been used for this purpose (Gilbert et al., 1977; Kroll and Table 1 (Characteristics of interaction for selected biocides Concentetion 263 Anagnostopoulos, 1981; Daham and Wiseman, 1987; Hugo and Denyer, 1987). Biocidal compounds derive from a variety of chemical classes; the precise mechanisms of interaction often reflect, this diversity although the final damaging outcomes may show considerable similarity (Table 2). Damage may be ‘manifest in the following ways: ¢ disruption of the transmembrane proton motive force leading to an uncoupling of oxidative phosphorylation and inhibition of active transport across the mem- brane; @ inhibition of respiration or catabolic/anabolic reac- tions; ‘¢ disruption of replication; ‘© loss of membrane integrity resulting in leakage of essential intracellular constituents such as potassium cation, inorganic phosphate, pentoses, nucleotides and nucleosides, and proteins; @ lysis; ¢ coagulation of intracellular material. ‘Taken in order, these lesions represent injury of increas- ing severity spanning bacteriostasis to rapid bactericidal action. Conventional theory recognises progressive injury arising from initial lesions and if the inimical challenge is maintained for sufficient duration or the applied con- centration is sufficiently high then initial bacteriostatic damage may develop to cause eventual cell death. Evidence is now accumulating to suggest thatthe tran- sition from sub-lethal injury to cell death may also arise following the initiation by biocide of self-destructive events. Metabolic imbalance following biocidal and other stresses has been postulated to lead to free radical pro- duction and self-destruction, a phenomenon which read- ily differentiates highly metabolically active exponentially growing cells from those in stationary phase (Dodd et a, 1997). Evidence for free radical action is provided by inducible oxyR protective effects (Greenberg and Demple, 1986; Chapman and Diehl, 1995), catalase- Inactivating neutralizing Example biocides exponent Site of of action ‘Type of interaction process Bronopol <2 Enzyme-SH Chemical Cysteine Qacs Membrane Tonic Lecithin + Tween 80, Formaldehyde ‘Amino groups Chemical Giycine Biguanides Membrane Tonic Lecithin +Tween 80 Sorbie acid a Enzyme-SH Chemical Dilution + Tween 80 Proton gradient Physical Ethanol >4 Membrane Physical Dilution Phenols Membrane Physical Dilution ‘Aromatic alcohols Membrane Physical Dilation 268 SP, Denver and G.S.A.B. Sway Table? /Incernational Biodeteroration & Biodegradation 41 (1998) 261-268 “Mechanisms of interaction of selected biocides with ther prospective targets and the consequential antibacterial effects Mechanisms of interaction Example biocides Chemica reactions: Oxidation of (predominantly) sothiazolinones "iol groups ‘organomercurial, heavy metal salts, hypochlorite, ‘organochlorine derivatives, beonopel, metallo-compounds (es. oxines) Gtutaraldehyde, formaldehyde (and by implication Formaldebyde-reeasing agents), chloroacetamide ‘Genera alkylation reactions Halogenation Hypochlorite, chlorine-reeasing agents Frec-radcal oxidation (ea, Hydrogen peroxide, peracetic hydroxyl radicals) acid Metal ion chelation EDTA, oxines Intercalation Aminoaeridines Ionic interactions: Electrostatic onic) interaction with phospholipids QACS, chlorhexidine, polyexamethylene biguanides Physical interaction: Penetration,partition into phospholipid bilayer: possible displacement of phospholipid ‘molecules: intramembrane ‘molecular cycling Solution of phospholipids Momibrane-protein solubilization Phenols, weak acids, parabens tetrachloroslicylaifige phenoxsethanol, fentichior, = phenylethanol Aliphatic alcohols Anionic surfactants ‘Typical targets Aatibacteral effect, ‘Thiol-containing cytoplasmic and ‘membrane-bound enzymes ¢8 dehydrogenases Metabolic iil Biomolecules (eg. protein, RNA, DNA) contzining amino imino, amide, carboxyl and thiol groups (nucleophiles), Intermolecular crosslinking may occur Metaboli and replicative intbition; possibly some cell wall damage Amino groups in proteins Metabolic inhibition Enzyme and protein thiol roups Metabolic inhibition Divalent cation-mediated outer ‘membrane integrity, principal target region Gram-negative cell wall (EDTA), Metal jon-equiring ‘enzyme processes Leakage; increased susceptibility to applied stress. Metabolic inbibition Intercalation between DNA base pairs Replcative injury Cytoplasmic membrane integrity: membrane-bound enzyme ‘envigonment ard function Leakage: respiratory inhibition: intracellular coagulation ‘Transmembrane pH gradient; membrane integrity Leakage; disruption of transport, respiratory and energy coupling processes Membrane integrity Leakage Cytoplasmic membrane integrity: Leakage, uncoupling of energy membrane-bound enzyme processes Isis fnvironment and function enhanced survival (Martin et al., 1976; Flowers et al. 1977; van Netten et al., 1984), and improved viable cell recovery in minimal media (Tang and Jackson, 1979; Gilbert, 1984), A mechanism of action involving free radical generation has been proposed for the biocides 2- bromo-2-nitropropane-1,3-diol (Bronopol; Stretton and Manson, 1973; Shepherd et al., 1988) and 5-chloro: methyl-isothiazolin-3-one (Chapman and Diehl, 1995). Thus the effect of a biocide may be supplemented by autocidal activity (Fig. 2, biocide 1); once initiated this process may account fora significant proportion of popu- lation death and may not be resolvable by conventional biocide neutralizers (Table 1). Mechanisms of action which may lead to such autocidal processes currently fall into two categories: free radical accumulation through ‘metabolic imbalance and impaired ionic homeostasis (Table 3) It might be postulated that many of the inhibi- tors of respiration and oxidative phosphorylation (Di ‘Table 3 Examples of autocidal eects ‘Autocidal effect. Initiating processes Free radical accumulation through metabolic imbalance ‘Anabolie suppression Enhanced catabolism Respiratory stimulation ‘Redox chain perturbation Impaired ionic homeostasis ‘Activation of latent ibonuceases SP. Denyer and G.S.A.B. Stewart/InemationalBiodetvioration & Biodegradation $1 (1998) 261-268 100 * Selective permeabili PERCENT changes LOSS OF * Competitive enzyme VIABILITY | inhibition o 4 265 © @ * Topological destruction + Enzyme denaturation * Cytoplasm coagulation Reversible Preventable Irreversible bacteriostatic autocidal bactericidal effect effect effect APPLIED BIOCIDE STRESS -> Fig, 2. Nature of the antibacterial effect arising from treatment with two classes of biocide, 1 and 2. Applied biocide stress may be repretented by concentration or contact time, Monte et al., 1984; Kroll and Patchett, 1991; Phillips- Jones and Rhodes-Roberts, 1991) might lie in the former category, while membrane-active agents precipitating potassium ion leakage and thereby affecting intracellular homeostasis may initiate autolysis through activation of latent ribonucleases (Denyer and Hugo, 1991b; Lambert & Smith 1976). Autocidal effect may be prevented or limited, for example by the addition of free radical detox- ifiers or by low temperature inhibition of autolytic enzymes (Denyer and Hugo, 19916), but presumably early action would be required to have any significant effect on survival. Biocides which have no effect on meta- bolic activity or cellular homeostasis are unlikely to pre- cipitate an autocidal process (Fig. 2, biocide 2); there is thus good reason to explore mechanisms of action in a search for this advantageous compounding effect. 5. Strategies to enhance mechanism of action With a knowledge of interaction chemistry and anti- bacterial lesions, strategies begin to emerge by which biocidal action may be improved. These may include approaches to enhance initial interaction or accumu- lation at target site, optimisation of synergistic biocidal combinations, or engaging the bacterium in a “part- nership" with the biocide to invoke autocidal processes 5.1. Enhanced interaction Leeming et al. (1997) have described the physisorption of isothiazolinone analogues to hydrophobic beads with an optimised hydrophile-lipophile balance to ensure direct donation to an approaching bacterium (Fig. 3). This permits the use of biocides with low water solubility but optimal partition characteristics for the Gram-nega- tive cell envelope. Preliminary studies indicate a bac- tericidal effect in excess of four decimal reductions against Pseudomonas aeruginosa. 5.2, Intracellular biocide delivery Substrate carriers may be employed to facilitate the intracellular accumulation of membrane-impermeable biocides. By employing Escherichia coli genetically engi- neered to bioluminesce, Denyer et al, (1991) have dem- onstrated the intracellular delivery of a range of novel * Presentation of biocide on demand from an immobilized support * Permits optimal hydrophilic- lipophilic balance aiding biocide uptake and penetration to target S.P. Denver and G-S.A.B. StewarInernasional Blodeterioraion & Biodegradation 41 (1988) 261-268 A ° (\ Fig. 3 Biocide donation from an immobilized support (modified from Leeming etal. 1997) phenolic derivatives of galactose via the Jac permease, Intracellular cleavage of biocide from the transported molecule resulted in cell damage and loss of metabolic function as indicated by reduced light output (Fig. 4). 5.3. Optimised biophysical} biochemical synergy The literature reports a variety of synergistic com- binations (for example, Lehmann (1988); a close exam- ination would suggest that a selection offer readily identifiable mutually supportive mechanisms of action (Denyer, 1996). Denyer et al, (1986) have demonstrated that the mechanism of synergy in biocide combinations can be investigated experimentally. Such a complex mul- tivariate data set requires statistical interpretation (Rabone and Harbron, personal communication) aided by simple factorial design for assessment of activity (Kar- abit et al., 1989). Close examination of mechanisms of action may thus offer a route to predicting and identifying 140 120 100 Bioluminescence % after 24h 6 incubation a as % of control 20 0 synergistic potential; a knowledge of the interactions involved will guide formulation design. 54, Autocidal effect The identification of an autocidal component to bioe- ide action offers an exciting challenge to the disinfectant Formulator. Metabolic imbalance arising from an “uncoupling” of anabolic and catabolic processes will be catalysed at sub-lethal biocide levels. Thus, this phenom- enon may become of greatest import in circumstances where biocide accumulation at target is limited and the calli still metabolically operational. Its therefore poss- ible to conceive of situations where controlled, possibly sequential, additions of biocides might initiate autocidal processes more efficiently than a high initial dose. What relevance also the autocidal process to the biofilm organ- ism, established to survive in a nutrient deplete environ- ment? Could we here present challenges to conventional Po PMPG PePG TEPG CPG PCONFG EPHEG Biocide Derivative Fig. 4. Bioluminescence Irom Escherichia cel pSB100 growing in the presence of selected f-D-galactopyranosie (G) derivatives of phenolic biocides. G, pheny!-G; PMPG. 4.methyipheny 4.chloro-2-nitophensL-G; EPHBG, chyl &-hydroxybenzoate-G. "BPG, 4-bromopheny/-G; TBPG, (4.8)-ribromopheny/-G: DCPG, 2.4-dichlorophensl-G: PCONPG. SP. Denyer and G-5.4.B. Stewart\Inemational Biodetevivation & Biodegradation 41 (1998) 261-268 267 wisdom: might deliberate metabolic activation of con- taminating organisms predispose to intracellular injury? 6. Conclusion The study of biocide mechanisms of action offers an, as yet, largely untapped initiator of novel development directions, Quantitative structure-activity relationships will provide unique insight into fruitful chemical per- mutations. Target identification will create a greater understanding of microbial survival mechanisms and give leads to their avoidance. Moreover, the association of autocidal events with disinfection processes may well offer new avenues for exploration. References Bloomfield, SF. 1991. Methods for Assessing Antimicrobial Activity Tn: Mechanisms of Action of Chemical Bicides: Theie Study and Exploitation, ed. SP. Denyer and W.B, Hugo, pp. 1-22. Blackwell Scientifie Publications, Oxford Brown, M.RW., Collie. PJ., Gilbert, P, 1990. Influence of growth rate susceptibility t0 antimicrobial agents: modification of the cell envelope and batch and continuous culture studies. Antimicrob, ‘Ag. Chemother. 34, 1623-1628. Boston, P.. Woodcock, P.M., Gilbert, P., 1984, Interaction of some polyhexamethylene biguanides and membrane phospholipids, in Escherichia coli. 3. Appl. Bacteriol. $7, 115-128, (Chapman, JS. Diehl, MA,, 1995. Methychloroisothiszolone-induced ‘growth ahibition and lethality in Escherichiaco.J. App. Bacteriol 78, 134-181 Daham, $.A.M., Wiseman, D,, 1987. The uptake of chlorhexidine by Escherichia colt and its efets on viability inthe absence and pees ence of EDTA. J. Pharm, Pharmacol, Suppl. 39, 16. Denyee, SP, 1990. Mechanisms of action af biocides. Int. Biodet, 26, 39-100. Denyer,$P. 1995. Mechanisms of action of antibecteial biocides, In. Biodet. Biodee.. pp. 224-245, Denyer.S.P. 1996, Development of preservative systems. In: Microbial ‘Quality Assurance in Cosmetics, Toiletries and Non-steile Pha maceuticals, ed, RM, Baied with S.F. Bloomfield, pp. 133-148 ‘Taylor and Francis, London Denyer, §P., Hugo, W.B., 19913, Mechanisms of Acton of Chemical ‘Bocides Their Study end Exploitation, ed. S. P. Denyer and W. B. Hugo, Blackwell Scientific Publications, Oxford. Denyer, .P. Hugo, W.B., 1991b, Biside-induced damage tothe bac> "eral cytoplasmic membrane. In: Mechanisms of Action of Chem cal Biocides Their Study and Exploitation, ed. SP. Denyer and Hugo, W.B., pp. 171-188. Blackwell Seientic Publications, Oxford. Denyer, SP. Hugo, W-B. Harding, V.D,, 1986. The biochemical basis Of synergy betwoen the antibacterial agents, chloroeresol and 2+ phenylethanol. Int. J. Pharmaceut. 29, 29-36 Denyer, SP, Jackson, D.E., AbSagher, M. 1981 Intracellular delivery ‘of biocides, In: Mechanisms of Action of Chemical Biocies: Their ‘Study and Exploitation, ed, §P. Denyer and WB. Hugo, pp. 263, 270, Blackwell Scientiie Publications, Oxford DiMonte, D, Bellomo. G, Thor. H., Nicotera, P., Orthenius,S., 1984, Menadione-induced cytoxcity is associated with protein thio! oxi dltion and alteration in intracelular calcium homeostasis. Arch Biochem. Biophys. 235, 43-350. Dodd, C.E.R., Sharman, KL. Bloomfeld, F., Booth, LR. Stewart, GSAB., 1997, Inimical processes: bacterial selidestruction and sublethal injury. Trends Food Sci. Techno, 8, 38-241 Flowers, R'S., Martin, SE, Brewer. B.G., Orda, Z1., 1977. Catalase and enumeration of stresed Staphylococcus aureus cells. App. Eas: Microbiol. 33, 1112-1117, Gilbert, P1988. The revival of micro-organisms sublethally injured by chemical inhibitors. In: The Revival of Injured Microbes, ed MLHLE. Andrew and A.D. Russell pp. 175-197. Academic Press, London Gilbert, P., ALTaxe, A., 1985. Antimicrobial ativity of some alkyl twimethylammonium bromides. Lett, Appl. Mieobiol. 1, 101-108 Girt, P., Wright, NE. 1987. Non-plasmidic resistance towards pres- ‘ervation of pharmaceutical products. In: Preservatives inthe Food. Pharmaceutical and Environmental Industries, ed. RG. Board, MC. Allwood and J.G, Banks, pp. 255-279. Blackwell Scientific Publications, Oxford. Gilbert, P, Beverdge, EG. Crone, PB. 1977. The lethal action of ‘Phenoxyethanol and its analogues upon Escherichia colt NCTC 5933, Microbios. 19, 125-141 Greenberg, 1:7, Demple, B, 1986, Glutathione in Escherichia cot is “ispensable for resistance to H.O; and gamma radiation, J. Bact 16, 1026-1029, Hugo, W.B., 1991. A brief history of heat and chemical preservation and disinfection. J. App. Bacteriol. 71, 9-18, ‘Hugo, W.B., 1992, Disinfection mechanisms In: Principles and Practice ‘of Disinfection, Preservation and Sterlisation, 2nd edition. ed. A.D. Russell, W.B. Hugo and GA. Aylife, pp. 187-210. Blackwell, Scientific Publications, Oxford Hugo, W.B., 1995. A brief history of heat, chemical and radiation preservation and disinfection, Int Biodet. Biodeg,, pp. 197-2 Hugo, W.B., Denyer, SP., 1987. The concentration exponent of dis- infectants and preservatives. In: Preservatives in the Food, Phar- ‘maceutical and Environmental Industries, ed. R.G. Board, M.C. Allwood and 1.G. Banks, pp. 281-292. Blackwell Scemtiie Pub- lations, Oxford Hugo, WB. Russell, A.D. 1992 Types of antimicrobial agents. In Principles and Practice of Disinfection, Preservation and Ste. lisation, 2nd edition. ed, A.D. Russell, W.B. Hugo and G.AJ “Ayilife, p. 7-88. Blackwell Scientific Publications, Oxford Kanazawa A., Ikeda, T., Endo, T, 195. A novel approach to mode ‘of action of eationie biocides: morphological effect on antibacterial activity. J. Appl. Bacteriol. 78, 55-60. Karabit, MS. Juneskans, O.T.. Lungren, P, 1989, Factorial designs inthe evaluation of preservative activity, Int. J. Pharmaceat. 56 169-174 Kroll, RG. Anagnostopoulos, G.D,, 1981, Potassium leakage as 2 lethality index of phenol and the effect of solute and water activity. 4. Appl. Bacteriol. 50, 139-147, Kroll, RG, Patchett, R.A., 1991. Biocideinduced perturbations of ‘aspects of cell homeostasis: intracellular pH, membrane potential ‘and solute transport. In: Mechanisms of Acton of Chemical Bioc- ‘ides: Their Stody and Exploitation, ed. SP. Denyer and W.B. Hugo, pp. 189-202 Blackwell Sciemtifle Publications, Oxford. Lambert, PA.. Smith, A.R.W., 1976, Antimicrabiat action of dode- ‘pldicthanolamine: atvation of ribonuclease Tin Escherichia col Microbios. 17, 35-49, Leeming, K», Moore, CP. Denyer. SP. 1997. The Bug Beater new ‘approach to the costrol of micro-organisms in photoprocesing applications, International Symposium on Silverhalie Imaging, Society for Imaging Science and Technology, Victoria, Canada Lehmans, RH, 1988, Synergisms in disinfectant formulations. In: Industrial Biocids, Critical Repor’s on Applied Chemistry, ed. K. R. Payne, Vol. 23. pp. 65-90, Wiley, Chichester. Manin, SE. Flowers, R'S., Ordal, 21.1976, Catalase: its effect on ‘microbial enumeration. Appl. Env. Microbiol 32, 732-734 Nica, Til, Hancock, R-EW., 1980. Outer membrane protcin HI of ‘Pselomonas aeruginosa: involvement in adaptive and mutational 268 SP. Denyer and G.8.A.B. Stewart resistance to ethylenediaminetetracetate, polymysin B and gen- ‘amicin J. Bacteriol. 143, 872-878. Paulus, W., 1991. Microbicides forthe protection of materials: yest ‘day, today and tomorrow. In: Biodeteriration and Biodegredation, ‘ed, H.W, Rossmoore, Vol. 8, pp. 35-52. Elsevier Applied Science Publishers, London, Paulus, W., 1993 Microbicides forthe Protection of Materials: « Hand: ‘book. Chapman and Hall, London, Philips Jones, M.K., Rhodes-Robers, MLE, 1991. Studies of inhibi- tors of respiratory electron transport and oxidative phos: phorylation. In: Mechanisms of Action of Chemical Biocies: Thee Study and Exploitation. ed. S.P. Denyer and W. B. Hugo, pp. 202— 224, Blackwell Scientific Publications, Oxford, Reichart,0., 1994, Modeling the destruction of Escherichia colion the ‘base of reaction kinoies. Int. J. Food Microbiol. 25. 489-468. Richards, RME,, Xing, D.K.L., King, TP, 1995. Activity of pamino. ‘benzoic acid compared with other organic acids agtinst selected bacteria. J. Appl. Bacteriol. 78, 29-215. Russell, A.D., 1991. Mechanisms of bacterial resistance to non-antc biotes: food additives and food and pharmaceutical preservative. J. Appl Bacteriol, 71, 191-201. Russell, A.D., Mortis, A. Allwood, M.C.. 1973, Methods for assessing ‘damage to bacteria induced by chemical and physical agents. Meth. Microbiol. 8, 95-182, international Biodetriration & Biodegradation 41 (1998) 261-268 Russell, A.D., Fars, LR. Maillad, J-¥,, 1997. Microbial susceptibility ‘and restance to biocides. ASM News, 63, 481487 Salton, M.RJ., Onen, P. 1976, Bacterial membrane structures. Ann Rev. Microbiol. 30, 451-482. ‘Shepherd .A., Waigh, R.D., Gilbert, P. 1988. Antibacterial action of 2sbromo-2-nitropropan-1.3-

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