7 Conclusions
An appreciation of the multi-faceted mechanisms through which antimicrobial drugs
can exert their therapeutic effects, including the interruption of bacterial communica-
tion systems, altering host immune responses, altering host inflammatory responses,
or interfering with pathogen virulence factors, will help to ensure that antimicrobial
drug substance, drug product formulation and dose selection are based on the
principles of prudent and rational use. Clinical and laboratory experiences point to
the conclusion that the adoption of these principles will be critical in prolonging the
life of our existing antimicrobial arsenal. However, in the final analysis, it is important
Table 4Examples of virulence factors and new therapeutic approaches for targeting these factors
(Periti and Mazzei 1998 ; Cegelski et al. 2008 ; Hanlon 2007 ; Liautard et al. 2006 ; Duckworth and
Gulig, 2002 ; Clatworthy et al. 2007 ; Marriott et al. 2008 ; Lynch and Wiener-Kronish 2008 ;
Schwegmann and Brombacher, 2008 ; Escaich 2008 ; del Pozo et al. 2009 )
Factor Mechanism of Action
Endotoxin Neutralising activity (e.g. fluoroquinolones, aminogylcosides,
glycopeptides)
Toxin Reduce toxin production
Reduce toxin delivery
Reduce host response to toxin
Antibody-based toxin neutralisation (anti-toxin antibodies, such as
the antibodies used against botulinum neurotoxin)
Cytolysin Counteract cytolysins (bacteria toxins that lead to lysis of host
cells)=.
Adhesion factors Inhibit bacterial formation of pili and fimbriae needed for adhesion
to cell surfaces (pilicides)
Quorum sensing See text
Cell integrity Bacteriophage
Type III secretions Antibodies binding to Type II injectosome ( a needle like
projection releasing toxins) and blocking toxin release
Bacterial species specific
adhesion proteins
Reduce likelihood of biofilm formation, and therefore risk of
chronic infections
Prevention of gene
expression
For example, virstatin is a novel compound that inhibits expression
of the toxT gene leading to the production of cholera toxin
Trojan horse strategy Tricks bacteria to sequester a biologically inactive transition metal
for Fe3+, thereby repressing iron-dependent transcript
Inhibition of intracellular
multiplication
Interfere with the synthesis of gene products needed for adaption to
intracellular environment (i.e. low O 2 tension, amino acid
starvation. Examples includeLegionella,Mycobacteriumand
Brucella)
Electrically induced
bactericidal activity
Low-intensity electrical current substantially reduced the numbers
of viable planktonic bacteria or those that reside within a
biofilm. This has been coined an “electricidal effect”. The
mechanism of action is unknown but has been suggested to
result from toxic substances, the oxidation of enzymes and
coenzymes, membrane damage leading to the leakage
cytoplasmic constituents, and/or a decreased bacterial
respiratory rateAntimicrobial Drug Resistance 257