Antibiotic and biocide resistance in bacteria: Introduction

A.D. Russell

Welsh School of Pharmacy, Cardiff University, UK

1 . S U M M A R Y

Drug resistance in bacteria is increasing and the pace at
which new antibiotics are being produced is slowing. It is
now almost commonplace to hear about methicillin-resist-
ant Staphylococcus aureus (MRSA), vancomycin-resistant
enterococci (VRE), multi-drug resistance in Mycobacterium
tuberculosis (MDRTB) strains and multi-drug-resistant
(MDR) Gram-negative bacteria. So-called new and emer-
ging pathogens add to the gravity of the situation. Reduced
susceptibility to biocides is also apparently increasing, but
is more likely to be low level in nature and to concentra-
tions well below those used in hospital, domestic an
industrial practice. A particular problem, however, is found
with bacteria and other micro-organisms present in
biofilms, where a variety of factors can contribute to
greater insusceptibility compared with cells in planktonic
culture. Also of potential concern is the possibility that
widespread usage of biocides is responsible for the selection
and maintenance of antibiotic-resistant bacteria. The basic
mechanisms of action of, and bacterial resistance to,
antibiotics are generally well documented, although data
continue to accumulate about the nature and importance of
efflux systems. In contrast, the modes of action of most
biocides are poorly understood and consequently, detailed
evaluation of bacterial resistance mechanisms is often
disappointing. During this Symposium, the mechanisms
of bacterial resistance to antibiotics and biocides are
discussed at length. It is hoped that this knowledge will
be used to develop newer, more effective drugs and
biocides that can be better and perhaps, on occasion, more
logically used to combat the increasing problem of bacterial
resistance.

2 . B A C T E R I A L R E S I S T A N C E
T O A N T I B I O T I C S

Bacterial resistance to antibiotics is a major therapeutic
problem (Levy 1992). Moreover, the pace at which new
chemotherapeutic drugs are being introduced into clinical
practice has slowed. It is now almost commonplace to hear
about methicillin-resistant Staphylococcus aureus (MRSA),
vancomycin-resistant enterococci (VRE), multi-drug resist-
ance in Mycobacterium tuberculosis (MDRTB) strains and
multi-drug-resistant (MDR) Gram-negative bacteria. Other
well known examples include penicillin resistance in
Neisseria gonorrhoeae, pneumococcal infections that are
resistant to penicillin or macrolide therapy, and drug-
resistant meningococci and Haemophilus influenzae (Table 1).
The outcome is that many antibiotics can no longer be used
for the treatment of infections caused by such organisms,
and the threat to the usage of other drugs is steadily
increasing (Table 1) (Courvalin 1996; Chopra 1998; Nikaido
1998; WHO 2000).

The gravity of the situation is compounded by the

emergence of epidemic, multi-antibiotic-resistant Burk-
holderia cepacia and Stenotrophomonas maltophilia (Spencer
1995).

3 . B A C T E R I A L R E S I S T A N C E T O B I O C I D E S

Reduced susceptibility to biocides is also apparently
increasing (McDonnell and Russell 1999; Russell 1999),
but is more likely to be low-level in nature and to
concentrations well below those used in hospital, domestic
and industrial practice. In actual fact, concern about the
resistance of Pseudomonas aeruginosa to cationic biocides was
expressed some 50 years ago (Lowbury 1951), with subse-
quent studies showing that many different types of bacteria
could gradually become less susceptible to most biocides
over long periods of time. This is amply demonstrated in the
report by Chapman (1998) in which he lists increased
insusceptibility to many biocides, including quaternary

1. Summary, 1S
2. Bacterial resistance to antibiotics, 1S
3. Bacterial resistance to biocides, 1S
4. Mechanisms of action of antibiotics and biocides, 2S

5. Mechanisms of bacterial resistance to antibiotics and

biocides, 2S

6. Overall comments, 3S
7. References, 3S

Correspondence to: Professor A.D. Russell, Welsh School of Pharmacy, Cardiff
University, Cardiff CF10 3XF, UK (e-mail: [e-mail]).

ª 2002 The Society for Applied Microbiology

Journal of Applied Microbiology Symposium Supplement 2002, 92, 1S–3S

ammonium compounds (QACs), chlorhexidine, phenolics,
heavy metals, and even aldehydes such as glutaraldehyde.

A particular problem is found with bacteria and other

micro-organisms present in biofilms, where a variety of
factors can contribute to the greater insusceptibility to
biocides compared with cells in planktonic culture (Lewis
2001). This is significant not only environmentally, e.g.
biofouling and biocorrosion, but also with implanted
medical devices, the infection with which may be difficult
to eradicate.

4 . M E C H A N I S M S O F A C T I O N
O F A N T I B I O T I C S A N D B I O C I D E S

The basic mechanisms of action of antibiotics are generally
well documented (Russell and Chopra 1996). They act as
inhibitors of peptidoglycan synthesis (e.g. b-lactams, glyco-
peptides), protein synthesis (tetracyclines, chloramphenicol,
mupirocin, macrolides, aminoglycosides-aminocyclitols) and
nucleic acid synthesis by interrupting nucleotide metabolism
(sulphonamides,

diaminopyrimidines),

inhibiting

RNA

polymerase (rifamycins), or inhibiting DNA gyrase (quinol-
ones). In addition, some antibiotics (polymyxins) interfere
with membrane integrity. In mycobacteria, isoniazid has to
be activated and then inhibits mycolic acid synthesis
(reviewed by Zheng and Young 1993).

By contrast, the mechanisms of the antibacterial action of

biocides are imperfectly understood. Biocides are known to
interact with bacterial cell walls or envelopes (e.g. glutar-
aldehyde), produce changes in cytoplasmic membrane
integrity (cationic agents), dissipate the proton-motive force

(pmf; organic acids and esters), inhibit membrane enzymes
(thiol interactors), act as alkylating agents (ethylene oxide),
cross-linking agents (aldehydes) and intercalating agents
(acridines), or otherwise interact with identifiable chemical
groups in the cell (Denyer and Stewart 1998). Biocides are
likely to have multiple target sites within a bacterial cell
(Denyer and Stewart 1998), although it has now been shown
(McMurry et al. 1998) that triclosan acts as a specific
inhibitor of enoyl reductase.

5 . M E C H A N I S M S O F B A C T E R I A L
R E S I S T A N C E T O A N T I B I O T I C S
A N D B I O C I D E S

Mechanisms of bacterial resistance to antibiotics are well
understood (Nikaido 1998). The ways in which bacteria
evade or overcome the action of drugs are too complex to
describe here in detail. Essentially, they involve reduced
antibiotic uptake (impermeability or efflux), drug degrada-
tion (enzymatic attack), modification of specific target sites,
overproduction of the target or bypass of the antibiotic-
sensitive step by duplication of the target site, the second
version being insusceptible (Levy 1992; Russell and Chopra
1996; Chopra 1998; Russell 1998). Resistance to isoniazid in
mycobacteria is primarily associated with the absence of an
enzyme-metabolic pathway such that the drug is not
converted intracellularly into its active form (Bardou et al.
1998).

Because the mechanisms of action of biocides are often

poorly understood (Section 4), detailed evaluation of
bacterial resistance mechanisms remains disappointing.

Infection

Antibiotic treatment no longer effective

Gonorrhoea

Low dose penicillin; sulphonamides

Bacillary dysentery

Most

Wound infections and

sepsis (Staphylococcus aureus)

Benzylpenicillin, b-lactamase-resistant penicillins

Meningitis

Neisseria meningitidis

Sulphonamides

Haemophilus influenzae

Ampicillin, chloramphenicol

Pneumonia

Streptococcus pneumoniae

Penicillin, others

Table 1 Examples of antibiotic therapies
that are no longer effective or are threatened

Bacterial resistance to

Antibiotics

Biocides

Impermeability

Impermeability

Efflux

Efflux

Modification of target site

Modification of target site or sites?

Drug inactivation

Biocide inactivation (mercury; others?)

Table 2 Major mechanisms of bacterial
resistance to antibiotics and biocides

2S

A . D . R U S S E L L

ª 2002 The Society for Applied Microbiology, Journal of Applied Microbiology Symposium Supplement, 92, 1S–3S

Nevertheless, it is known that at least some (efflux,
impermeability, modification of target sites) of the general
mechanisms responsible for antibiotic resistance are also
applicable to biocides (Table 2). The possibility exists of
‘cross-resistance’ arising between antibiotics and biocides.

6 . O V E R A L L C O M M E N T S

The inexorable rise in antibiotic-resistant bacteria, the
comparative dearth of new therapeutic agents and the
apparent increase in biocide resistance paint a gloomy
picture.

Speakers

in

this

symposium

consider

target

sites

(including novel ones) for antibacterial action, the mech-
anism of bacterial resistance, the importance of resistance
in the medical, veterinary and food industries and the
thorny issue of biocide usage and possible antibiotic
resistance.

7 . R E F E R E N C E S

Bardou, F., Raynaud, C., Ramos, C., Lane´elle, M.A. and Lane´elle, G.

(1998) Mechanism of isoniazid uptake in Mycobacterium tuberculosis.
Microbiology 144, 2539–2544.

Chapman, J.S. (1998) Characterizing bacterial resistance to preserva-

tives and disinfectants. International Biodeterioration and Biodegra-
dation 41, 241–245.

Chopra, I. (1998) Research and development of antibacterial agents.

Current Opinion in Microbiology 1, 495–501.

Courvalin, P. (1996) Evasion of antibiotic action by bacteria. Journal of

Antimicrobial Chemotherapy 37, 855–869.

Denyer, S.P. and Stewart, G.S.A.B. (1998) Mechanisms of action of

disinfectants. International Biodeterioration and Biodegradation 41,
261–268.

Levy, S.B. (1992) The Antibiotic Paradox. How Miracle Drugs Are

Destroying the Miracle. New York: Plenum Press.

Lewis, K. (2001) Riddle of biofilm resistance. Antimicrobial Agents and

Chemotherapy 45, 997–1007.

Lowbury, E.J.L. (1951) Contamination of cetrimide and other fluids with

Pseudomonas pyocyanea. British Journal of Industrial Medicine 8, 22–25.

McDonnell, G. and Russell, A.D. (1999) Antiseptics and disinfectants:

activity, action and resistance. Clinical Microbiology Reviews 12, 147–
179.

McMurry, L.M., Oethinger, M. and Levy, S.B. (1998) Triclosan

targets lipid synthesis. Nature 394, 531–532.

Nikaido, H. (1998) Multiple antibiotic resistance and efflux. Current

Opinion in Microbiology 1, 516–523.

Russell, A.D. (1998) Mechanisms of bacterial resistance to antibiotics

and biocides. Progress in Medicinal Chemistry 35, 133–197.

Russell, A.D. (1999) Bacterial resistance to disinfectants: present

knowledge and future problems. Journal of Hospital Infection 43
(Suppl.), S57–S68.

Russell, A.D. and Chopra, I. (1996) Understanding Antibacterial Action

and Resistance 2nd edn. Chichester: Ellis Horwood.

Spencer, R.S. (1995) The emergence of epidemic, multiple-antibiotic-

resistant Stenotrophomonas (Xanthomonas) maltophilia and Burk-
holderia (Pseudomonas) cepacia. Journal of Hospital Infection 30
(Suppl.), S453–S464.

WHO (2000) Overcoming Antimicrobial Resistance. World Health

Organization Report on Infectious Diseases. Geneva: WHO.

Zheng, Y. and Young, D.B. (1993) Molecular mechanism of isoniazid:

a drug at the front line of tuberculosis control. Trends in Microbiology
1, 109–113.

B A C T E R I A L R E S I S T A N C E : I N T R O D U C T I O N

3S

ª 2002 The Society for Applied Microbiology, Journal of Applied Microbiology Symposium Supplement, 92, 1S–3S