Antibiotic resistance: an increasing problem?

Dear Sir,

Evidence is now available to the effect that continued use of a
given antibiotic for control and/or degradation of bacterial
populations in mammalian metabolisms eventually results in a
decrease in the extent of control. The origin of this phenomenon is
presently considered to be the presence in any bacterial
population of alternative forms, or the generation of alternative
forms, of the bacteria which produce chemical compounds which
degrade the antibiotic being used. In the case of penicillin for
example such versions of the bacteria involved are advanced as
capable of developing the capacity to produce b-lactamase
(penicillinase) when brought into contact with penicillin.

It is
proposed that penicillin is destroyed by b-lactamase. Although
some bacteria produce this compound this is not the case for most
bacteria. Penicillinase-resistant b-lactam antibiotics such as
methicillin have been developed. However resistance to these has
also arisen. Penicillium chrysogenum is a mold that is widely
distributed in nature and is the source of penicillin and several
other b-lactam antibiotics which allow the mold to be active against
several bacteria. As stated only a few bacteria in nature exhibit b-
lactam resistance. On the basis that this mold and bacteria have
been interacting for millennia the absence of a widespread
development of b-lactam resistance among bacteria in nature
indicates that the development of this phenomena is the result of
either the different chemical environment of the mammalian
metabolism and/or that the mammalian metabolism contains a
factor or factors either absent from or present in the latter
environment. The fact that Penicillium chrysogenum produces a
family of b-lactams only one of which is separated and used in
mammalian metabolisms is the possible reason for the
development of antibiotic resistance in these systems. The family
of antibiotics produced and used simultaneously against bacteria
in nature by molds ensures that degradation of susceptible
bacteria takes place from several chemical directions. The
persistent use of a single member of the Penicillium chrysogenum
family of b-lactams means that an alteration in bacterial cell
chemical reactions can lead to the the incorporation of derivatives
of penicillin as part of the cell structure. For example penicillin may
be regarded as being derived from D-bb-Methylcysteine and the
N-acetyl derivatives of serine aldehyde which have combined to
form thio-amino acetals (penicilloic acids), followed by dehydration
to give the b-lactam. Hydrolysis, the reversal of this process, is
likely to result in the reformation of these compounds which are
amino acids and can be incorporated into the structure of cell
proteins without having any effect. Persistent long term contact
with penicillin can also lead to the alteration of the chemical
reactions in a bacterial cell giving rise to a novel products. Such
contact can occur under conditions where the concentration of
penicillin is below that required for effective degradation of a
bacterial cell. The continued division of the bacterial cell further
reduces the concentration of antibiotic compound by factor of two
after each division (e.g. after 10 divisions the concentration in any
part of a bacterium is reduced by a factor of one thousand)
although the concentration is never reduced to zero. The
persistence of these low concentration conditions over an
extended period of time accompanied by withdrawal of contact
with higher concentrations of penicillin means the bacteria
involved can incorporate the antibiotic or the products of antibiotics
into the cellular chemical reactions giving rise to novel cell
compounds, one of which is b-lactamase. In Penicillium
chrysogenum the simultaneous presence of a family of b-lactams
inhibits these occurrences almost certainly by the presence of
competing chemical reactions, this being analogous to the use of a
mixture of venoms by some reptiles. It would therefore appear that
the use of a related family of antibiotic compounds all derived from
the same source and not a heterogeneous mixture might well
extend the effective lifetime of the b-lactam antibiotic compounds.

D.S. Robertson , Malvern, Worcestershire, England.

Competing interests:
None declared