Biomedical Engineering Reference
In-Depth Information
resistance; and (c) extrachromosomal acquired resistance, which is disseminated by plasmids or
transposons. The i rst type of resistance can be due to the inaccessibility of the target, the presence
of a multidrug efl ux system, or due to inactivation of the antibiotic. The mutational resistance, like-
wise, may be of different origin. This resistance may be due to a reduced permeability or uptake, a
metabolic bypass, a modii cation of the target site, or a repression of the multidrug efl ux system.
The third type of resistance may be caused by drug inactivation, target site modii cation, metabolic
by-pass, or the efl ux system. The existence of multidrug-resistance efl ux pumps is the major mech-
anism of intrinsic and acquired resistance of bacteria against a variety of different antibiotics. The
resistance-nodulation-cell-division (RND) family of transporters form a large multiprotein complex
that transverse the inner and outer membrane of Gram-negative bacteria through the periplasmic
region. Inhibition of the efl ux pumps could be used in combination with antibiotics and a variety
of such compounds have been identii ed. It has been observed that antibacterial targets, that give
rise to low occurrence of resistance through single-step mutation, are of made of multiple genes or
are structures that are synthesized by multiple genes. Antibacterials targeting single enzymes easily
give rise to high-level resistance and are best used in combination therapy.
Another important observation is that most bacterial infections contain nonmultiplying bacteria
that are resistant to treatment with antimicrobial drugs. They could exist as spores, in a dormant
state, or in a clinically latent situation. The best-known example of a clinically latent bacterium is
the
Mycobacterium tuberculosis
. The use of drugs that target nonmultiplying bacteria should result
in shorter treatment periods and, hence, a lower level of resistance. Some of the known antibiotics
(i.e., penems, nocardicin A, some quinolines, rifampicins) are able to kill some nonmultiplying
bacteria.
25.11 CONCLUDINGREMARKS
Development of antibiotics is one of the oldest i elds in medicinal chemistry and antibiotics have
saved uncountable lives of human beings during the last 60 years. It is a research domain that has
been neglected during the last two decennia with serious consequences. The bugs are i ghting back
and they have learned how to defend themselves against their killers. There is an urgent need for
new antibacterials with new mode of actions. Likewise, the way of discovery of new antibacterials
should be altered. In the past, this was mainly focused on the discovery of inhibitors of bacterial
growth. The example of tuberculosis shows that this is not sufi cient. The main problem is that the
development of new antibiotics is one of the difi cult i elds of medicinal chemistry. Using leads from
nature combined with medicinal chemistry to inl uence the spectrum and the pharmacokinetics of
the natural compounds will remain one of the most important ways to develop new antibiotics.
FURTHER READINGS
E. Breukink and B. de Kruiff. Lipid II as a target for antibiotics.
Nat Rev Drug Discov
. 5, 321-332, 2006.
A.E. Clatworthy, E. Pierson, and D.T. Hung. Targeting virulence: A new paradigm for antimicrobial therapy.
Nat Chem Biol
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A. Coates, Y. Hu, R. Bax, and C. Page. The future challenges facing the development of new antimicrobial
drugs.
Nat. Rev. Drug Discov
. 1, 895-910, 2002.
O. Lomovskaya, H.I. Zgurskayal, M. Totrov, and W.J. Watkins. Waltzing transporters and 'the dance macabre'
between humans and bacteria.
Nat. Rev. Drug Discov
. 6, 56-65, 2007.
D.J. Payne, M.N. Gwynn, D.J. Holmes, and D.L. Pompliano. Drugs for bad bugs: Confronting the challenges
of antibacterial discovery.
Nat. Rev. Drug Discov
. 6, 29-40, 2007.
L.L. Silver. Multi-targeting by monotherapeutic antibacterials.
Nat. Rev. Drug Discov
. 6, 41-55, 2007.
P.A. Smith and F.E. Romesberg. Combating bacteria and drug resistance by inhibiting mechanisms of persis-
tence and adaptation.
Nat Chem Biol
. 3, 549-556, 2007.